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3. Glutathione transferases
Hayes JD, Flanagan JU, Jowsey IR.
Annu Rev Pharmacol Toxicol. 2005;45:51-88.
This review describes the three mammalian glutathione transferase (GST)
families, namely cytosolic, mitochondrial, and microsomal GST, the
latter now designated MAPEG. Besides detoxifying electrophilic
xenobiotics, such as chemical carcinogens, environmental pollutants,
and antitumor agents, these transferases inactivate endogenous
alpha,beta-unsaturated aldehydes, quinones, epoxides, and
hydroperoxides formed as secondary metabolites during oxidative stress.
These enzymes are also intimately involved in the biosynthesis of
leukotrienes, prostaglandins, testosterone, and progesterone, as well
as the degradation of tyrosine. Among their substrates, GSTs conjugate
the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2
(15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they
antagonize expression of genes trans-activated by the peroxisome
proliferator-activated receptor gamma (PPARgamma) and nuclear
factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of
15d-PGJ2, GST may enhance gene expression driven by nuclear
factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic
polymorphisms and this variation can increase susceptibility to
carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG
are associated with alterations in lung function and increased risk of
myocardial infarction and stroke. Targeted disruption of murine genes
has demonstrated that cytosolic GST isoenzymes are broadly
cytoprotective, whereas MAPEG proteins have proinflammatory activities.
Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression
of transferases in the Alpha, Mu, and Pi classes, an observation
suggesting they are part of an adaptive mechanism that responds to
endogenous chemical cues such as 4-hydroxynonenal and tyrosine
degradation products. Consistent with this hypothesis, the promoters of
cytosolic GST and MAPEG genes contain antioxidant response elements
through which they are transcriptionally activated during exposure to
Michael reaction acceptors and oxidative stress.
PMID: 15822171
4. Glutathione
Jefferies H et al.
ANZ J Surg. 2003 Jul;73(7):517-22.
Glutathione (GSH) is an ubiquitous thiol-containing tripeptide that
plays a key role in cell biology. It modulates cell response to redox
changes associated with the reactive oxygen species, detoxifies the
metabolites of drugs; regulates gene expression and apoptosis, and is
involved in the transmembrane transport of organic solutes.
Polymorphism has been observed in key enzymes of GSH metabolism and
some alleles have been associated with an impaired redox buffer system
downsteam diseases, and susceptibility to ischaemia. These varied
activities make GSH an attractive target for a more reductionist
approach to the prevention and management of many conditions of
interest to surgeons.
PMID: 12864828
5. Glutathione S-transferase polymorphisms and their biological consequences
Hayes JD, Strange RC.
Pharmacology. 2000 Sep;61(3):154-66.
Two supergene families encode proteins with glutathione S-transferase
(GST) activity: the family of soluble enzymes comprises at least 16
genes; the separate family of microsomal enzymes comprises at least 6
genes. These two GST families are believed to exert a critical role in
cellular protection against oxidative stress and toxic foreign
chemicals. They detoxify a variety of electrophilic compounds,
including oxidized lipid, DNA and catechol products generated by
reactive oxygen species-induced damage to intracellular molecules. An
increasing number of GST genes are being recognized as polymorphic.
Certain alleles, particularly those that confer impaired catalytic
activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased
sensitivity to toxic compounds. GST polymorphisms may be disease
modifying; for example, in subgroups of patients with basal cell
carcinoma or bronchial hyper-responsiveness, certain GST appear to
exert a statistically significant and biologically relevant impact on
disease susceptibility. Copyright 2000 S. Karger AG, Basel
PMID: 10971201
6. Glutathione-S-transferase family of enzymes
Strange RC et al.
Mutat Res. 2001 Oct 1;482(1-2):21-6.
The loci encoding the glutathione-S-transferase (GST) enzymes comprise
a large supergene family located on at least seven chromosomes. The
function of the GST enzymes has traditionally been considered to be the
detoxication of electrophiles by glutathione conjugation. A wide
variety of endogenous (e.g. by-products of reactive oxygen species
activity) and exogenous (e.g. polycyclic aromatic hydrocarbons)
electrophilic substrates have been identified. Interestingly, recent
data has suggested a role, at least for the pi class gene product, in
jun kinase inhibition. Since many GST genes are polymorphic, there has
been considerable interest in determining whether particular allelic
variants are associated with altered risk (or outcome) of a variety of
diseases...
7. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450,
glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to
xenobiotic metabolism and toxicity
Wormhoudt LW, Commandeur JN, Vermeulen NP.
Crit Rev Toxicol. 1999 Jan;29(1):59-124.
In this review, an overview is presented of the current knowledge of
genetic polymorphisms of four of the most important enzyme families
involved in the metabolism of xenobiotics, that is, the
N-acetyltransferase (NAT), cytochrome P450 (P450),
glutathione-S-transferase (GST), and microsomal epoxide hydrolase (mEH)
enzymes. The emphasis is on two main topics, the molecular genetics of
the polymorphisms and the consequences for xenobiotic metabolism and
toxicity. Studies are described in which wild-type and mutant alleles
of biotransformation enzymes have been expressed in heterologous
systems to study the molecular genetics and the metabolism and
pharmacological or toxicological effects of xenobiotics. Furthermore,
studies are described that have investigated the effects of genetic
polymorphisms of biotransformation enzymes on the metabolism of drugs
in humans and on the metabolism of genotoxic compounds in vivo as well.
The effects of the polymorphisms are highly dependent on the enzyme
systems involved and the compounds being metabolized. Several
polymorphisms are described that also clearly influence the metabolism
and effects of drugs and toxic compounds, in vivo in humans. Future
perspectives in studies on genetic polymorphisms of biotransformation
enzymes are also discussed. It is concluded that genetic polymorphisms
of biotransformation enzymes are in a number of cases a major factor
involved in the interindividual variability in xenobiotic metabolism
and toxicity. This may lead to interindividual variability in efficacy
of drugs and disease susceptibility.
PMID: 10066160
8. Effect of glutathione S-transferase M1 polymorphisms on biomarkers of exposure and effects
Srám RJ.
Environ Health Perspect. 1998 Feb;106 Suppl 1:231-9.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1533289&blobtype=pdf
Genotypes responsible for interindividual differences in ability to
activate or detoxify genotoxic agents are recognized as biomarkers of
susceptibility. Among the most studied genotypes are human glutathione
transferases. The relationship of genetic susceptibility to biomarkers
of exposure and effects was studied especially in relation to the
genetic polymorphism of glutathione S-transferase M1 (GSTM1). For this
review papers reporting the effect of GSTM1 genotype on DNA adducts,
protein adducts, urine mutagenicity, Comet assay parameters,
chromosomal aberrations, sister chromatid exchanges (SCE), micronuclei,
and hypoxanthine-guanine phosphoribosyl transferase mutations were
assessed... The relationship between genotypes and
biomarkers of exposure and effects may provide an important guide to
the risk assessment of human exposure to mutagens and carcinogens.
PMID: 9539016
9. Diet, genetic polymorphisms, detoxification, and health risks
Lampe JW.
Altern Ther Health Med. 2007 Mar-Apr;13(2):S108-11.
Modulation of detoxification enzymes is one mechanism by which diet may
influence risk of cancer and other diseases. However, genetic
differences in taste preference, food tolerance, nutrient absorption,
and metabolism and response of target tissues all potentially influence
the effect of diet on disease risk. Thus, disease prevention at the
individual and population level needs to be evaluated in the context of
the totality of genetic background and exposures to both causative
agents and chemopreventive compounds. Polymorphisms in the
detoxification enzymes that alter protein expression and/or function
can modify risk in individuals exposed to the relevant substrates. Diet
is a mixture of carcinogens, mutagens, and protective agents that are
all metabolized by detoxification enzymes. Genotypes associated with
more favorable handling of carcinogens may be associated with less
favorable handling of phytochemicals. For example, glutathione
S-transferases (GST) detoxify polycyclic aromatic hydrocarbons present
in grilled meats. GSTs also conjugate isothiocyanates, the
chemopreventive compounds found in cruciferous vegetables.
Polymorphisms in the GSTM1 and GSTT1 genes result in complete lack of
GSTM1-1 and GSTT1-1 proteins, respectively. In some observational
studies of cancer, cruciferous vegetable intake confers greater
protection in individuals with these polymorphisms; however, in other
studies, the converse is observed. A recent study of sulforaphane
pharmacokinetics suggests that lack of the GSTM1 enzyme is associated
with more rapid excretion of sulforaphane. Many phytochemicals are also
conjugated with glucuronide and sulfate moieties, and are excreted in
urine and bile. Polymorphisms in UDP-glucuronosyltransferases (UGT) and
sulfotransferases (SULT) may contribute to the variability in
phytochemical clearance and efficacy. The effects of UGT polymorphisms
on flavonoid clearance have not been examined, but UGT polymorphisms
affect glucuronidation of several drugs and steroid hormones. Genetic
polymorphisms in detoxification enzymes may account in part for
individual variation in disease risk but have to be considered in the
context of other aspects of human genetics, gut bacterial genetics, and
environmental exposures.
PMID: 17405687
10. Polyphenols and glutathione synthesis regulation
Moskaug JØ, Carlsen H, Myhrstad MC, Blomhoff R.
Am J Clin Nutr. 2005 Jan;81(1 Suppl):277S-283S.
http://www.ajcn.org/cgi/content/full/81/1/277S
Polyphenols in food plants are a versatile group of phytochemicals with
many potentially beneficial activities in terms of disease prevention...
Evidently, glutathione is important in many
diseases, and regulation of intracellular glutathione concentrations
may be one mechanism by which diet influences disease development. The
aim of this review is to discuss some of the mechanisms involved in the
glutathione-mediated, endogenous, cellular antioxidant defense system,
how its possible modulation by dietary polyphenols such as flavonoids
may influence disease development, and how it can be studied with in
vivo imaging.
PMID: 15640491
11. Inborn errors in the metabolism of glutathione
Ristoff E, Larsson A.
Orphanet J Rare Dis. 2007 Mar 30;2:16.
http://www.ojrd.com/content/2/1/16
Glutathione is a tripeptide composed of glutamate, cysteine and
glycine. Glutathione is present in millimolar concentrations in most
mammalian cells and it is involved in several fundamental biological
functions, including free radical scavenging, detoxification of
xenobiotics and carcinogens, redox reactions, biosynthesis of DNA,
proteins and leukotrienes, as well as
neurotransmission/neuromodulation. Glutathione is metabolised via the
gamma-glutamyl cycle, which is catalyzed by six enzymes. In man,
hereditary deficiencies have been found in five of the six enzymes.
Glutathione synthetase deficiency is the most frequently recognized
disorder and, in its severe form, it is associated with hemolytic
anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system
(CNS) damage and recurrent bacterial infections. Gamma-glutamylcysteine
synthetase deficiency is also associated with hemolytic anemia, and
some patients with this disorder show defects of neuromuscular function
and generalized aminoaciduria. Gamma-glutamyl transpeptidase deficiency
has been found in patients with CNS involvement and glutathionuria.
5-Oxoprolinase deficiency is associated with 5-oxoprolinuria but
without a clear association with other symptoms. Dipeptidase deficiency
has been described in one patient. All disorders are very rare and
inherited in an autosomal recessive manner. Most of the mutations are
leaky so that many patients have residual enzyme activity. Diagnosis is
made by measuring the concentration of different metabolites in the
gamma-glutamyl cycle, enzyme activity and in glutathione synthetase and
gamma-glutamylcysteine synthetase deficiency, also by mutation
analysis. Prenatal diagnosis has been preformed in glutathione
synthetase deficiency. The prognosis is difficult to predict, as few
patients are known, but seems to vary significantly between different
patients. The aims of the treatment of glutathione synthesis defects
are to avoid hemolytic crises and to increase the defense against
reactive oxygen species. No treatment has been recommended for
gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase
deficiency.
PMID: 17397529
12. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization
Westphal GA et al.
Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.
OBJECTIVE: Thimerosal is an important preservative in vaccines and
ophthalmologic preparations. The substance is known to be a type IV
sensitizing agent. High sensitization rates were observed in
contact-allergic patients and in health care workers who had been
exposed to thimerosal-preserved vaccines. There is evidence for the
involvement of the glutathione system in the metabolism of thimerosal
or its decomposition products (organomercury alkyl compounds). Thus
detoxification by polymorphically expressed glutathione S-transferases
such as GSTT1 and GSTM1 might have a protective effect against
sensitization by these substances. METHODS: To address this question, a
case control study was conducted, including 91 Central European
individuals with a positive patch-test reaction to thimerosal. This
population was compared with 169 healthy controls and additionally with
114 individuals affected by an allergy against para-substituted aryl
compounds. The latter population was included in order to test whether
possible associations were due to substance-specific effects, or were a
general feature connected with type IV immunological diseases.
Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase
chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was
significantly more frequent among patients sensitized to thimerosal
(65.9%, P = 0.013) compared with the healthy control group (49.1%) and
the "para-compound" group (48%, P = 0.034). Glutathione S-transferase
T1 deficiency in the thimerosal/mercury group (19.8%) was barely
elevated versus healthy controls (16.0%) and the "para-compound" group
(14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more
frequent among thimerosal-sensitized patients than in healthy controls
(17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6%
vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme
deficiencies (healthy controls vs. thimerosal GSTM1 negative
individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1],
GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the
glutathione-dependent system was repeatedly shown to be involved in the
metabolism of thimerosal decomposition products, the observed
association may be of functional relevance.
PMID: 11007341
13. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal
Müller M et al.
Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.
We have investigated the interaction of thimerosal, a widely used
antiseptic and preservative, with the human erythrocytic GST T1
(glutathione-S-transferase T1). This detoxifying enzyme is expressed in
the erythrocytes of solely the human species and it displays a genetic
polymorphism. Due to this polymorphism about 25% of the individuals of
the caucasian population lack this activity ("non-conjugators"), while
75% show it ("conjugators") (Hallier, E., et al., 1993). Using our
newly developed HPLC-fluorescence detection assay (Müller, M., et al.,
2001) we have profiled the kinetics of enzyme inhibition in erythrocyte
lysates of two individuals previously identified as "normal conjugator"
(medium enzyme activity) and "super-conjugator" (very high activity).
For the normal conjugator we have determined a 2.77 mM thimerosal
concentration to inhibit 50% of the GST T1 activity. In the case of the
super-conjugator a 2.3 mM thimerosal concentration causes a 50%
inhibition of the enzyme activity. For both phenotypes a 14.8 mM
thimerosal concentration results in residual enzyme activities equal to
those typically detected in non-conjugator lysates. Thus, sufficiently
high doses of thimerosal may be able to change the phenotypic status of
an individual--at least in vitro--by inhibition of the GST T1 enzyme.
PMID: 11556154
15. Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes
Westphal GA et al.
Arch Toxicol. 2003 Jan;77(1):50-5.
Thimerosal is a widely used preservative in health care products,
especially in vaccines. Due to possible adverse health effects,
investigations on its metabolism and toxicity are urgently needed. An
in vivo study on chronic toxicity of thimerosal in rats was
inconclusive and reports on genotoxic effects in various in vitro
systems were contradictory. Therefore, we reinvestigated thimerosal in
the cytochalasin B block micronucleus test. Glutathione S-transferases
were proposed to be involved in the detoxification of thimerosal or its
decomposition products. Since the outcome of genotoxicity studies can
be dependent on the metabolic competence of the cells used, we were
additionally interested whether polymorphisms of glutathione
S-transferases (GSTM1, GSTT1, or GSTP1) may influence the results of
the micronucleus test with primary human lymphocytes. Blood samples of
six healthy donors of different glutathione S-transferase genotypes
were included in the study. At least two independent experiments were
performed for each blood donor. Significant induction of micronuclei
was seen at concentrations between 0.05-0.5 micro g/ml in 14 out of 16
experiments. Thus, genotoxic effects were seen even at concentrations
which can occur at the injection site. Toxicity and toxicity-related
elevation of micronuclei was seen at and above 0.6 micro g/ml
thimerosal. Marked individual and intraindividual variations in the in
vitro response to thimerosal among the different blood donors occurred.
However, there was no association observed with any of the glutathione
S-transferase polymorphism investigated. In conclusion, thimerosal is
genotoxic in the cytochalasin B block micronucleus test with human
lymphocytes. These data raise some concern on the widespread use of
thimerosal.
PMID: 12491041
16. Population genetic approaches to neurological disease: Parkinson's disease as an example
Gandhi S et al.
Philos Trans R Soc Lond B Biol Sci. 2005 Aug 29;360(1460):1573-8.
http://journals.royalsociety.org/content/4emfvuqyahuexwcb/
Parkinson's disease (PD) is a common, progressive, incurable disabling
condition. The cause is unknown but over the past few years tremendous
progress in our understanding of the genetic bases of this condition
has been made. To date, this has almost exclusively come from the study
of relatively rare Mendelian forms of the disease and there are no
currently, widely accepted common variants known to increase
susceptibility.The role that the "Mendelian" genes play in common
sporadic forms of PD is unknown. Moreover, most studies in PD can
really be described as candidate polymorphism studies rather than true
and complete assessments of the genes themselves. We provide a model of
how one might tackle some of these issues using Parkinson's disease as
an illustration. One of the emerging hypotheses of gene environment
interaction in Parkinson's disease is based on drug metabolizing (or
xenobiotic) enzymes and their interaction with putative environmental
toxins. This motivated us to describe a tagging approach for an
extensive but not exhaustive list of 55 drug metabolizing enzyme genes.
We use these data to illustrate the power, and some of the limitations
of a haplotype tagging approach. We show that haplotype tagging is
extremely efficient and works well with only a modest increase in
effort through different populations. The tagging approach works much
less well if the minor allele frequency is below 5%. However, it will
now be possible using these tags to evaluate these genes
comprehensively in PD and other neurodegenerative conditions.
PMID: 16096106
17. The nuclear pregnane X receptor regulates xenobiotic detoxification
Kliewer SA.
J Nutr. 2003 Jul;133(7 Suppl):2444S-2447S.
http://jn.nutrition.org/cgi/content/full/133/7/2444S
The pregnane X receptor (PXR), which is a member of the nuclear
receptor family of ligand-activated transcription factors, is an
integral component of the body's defense mechanism against toxic
xenobiotics. PXR is activated by a broad spectrum of lipophilic
xenobiotics including prescription drugs, herbs, pesticides, endocrine
disruptors and other environmental contaminants. The promiscuous
ligand-binding properties of PXR are facilitated by the large volume
and smooth shape of its ligand-binding pocket. PXR binds to DNA as a
heterodimer with the 9-cis retinoic acid receptor (RXR) and regulates a
large number of genes involved in the detoxification and excretion of
toxic substances. Although PXR evolved to protect the body, its
activation by various prescription drugs and herbs such as St. John's
wort represents the molecular basis for an important class of drug-drug
interactions. Assays that detect PXR activation can now be used to
predict and prevent these drug-drug interactions.
PMID: 12840222
18. Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals
Sato M, Kondoh M.
Tohoku J Exp Med. 2002 Jan;196(1):9-22.
http://www.jstage.jst.go.jp/article/tjem/196/1/196_9/_article
Metallothionein (MT) is a ubiquitous, cysteine-rich, metal-binding
protein. MT synthesis is induced by various stimuli such as cadmium,
mercury, zinc, oxidative stress, glucocorticoid, and anticancer agents.
Recently, transgenic mice with loss-of-function mutations in the
MT-I/-II genes were established. It has been assumed that MT plays a
role in the detoxification of heavy metals. In recent studies using
MT-null mice, the ability of MT to protect against cadmium-induced
renal, liver and bone injuries has been confirmed. Moreover, MT is also
capable of scavenging oxygen free radicals. MT is involved in the
protection of tissues against various forms of oxidative injury,
including radiation, lipid peroxidation, oxidative stress caused by
anticancer drugs, and conditions of hyperoxia. However, MT still lacks
an established biological function. Unexpectedly, the MT-null mice were
apparently in good health, and the critical biological roles of MT have
been questioned. MT seems to be a protective protein produced in
response to a variety of stresses. Here, current studies on the
protective roles of MT against toxicity of heavy metals and reactive
oxygen species are reviewed, and the putative biological functions of
MT are discussed.
PMID: 12498322
19. Sulfation through the looking glass--recent advances in sulfotransferase research for the curious
Coughtrie MW.
Pharmacogenomics J. 2002;2(5):297-308. m.w.h.coughtrie@dundee.ac.uk
http://www.nature.com/tpj/journal/v2/n5/full/6500117a.html
Members of the cytosolic sulfotransferase (SULT) superfamily catalyse
the sulfation of a multitude of xenobiotics, hormones and
neurotransmitters. Humans have at least 10 functional SULT genes, and a
number of recent advances reviewed here have furthered our
understanding of SULT function. Analysis of expression patterns has
shown that sulfotransferases are highly expressed in the fetus, and
SULTs may in fact be a major detoxification enzyme system in the
developing human. The X-ray crystal structures of three SULTs have been
solved and combined with mutagenesis experiments and molecular
modelling, they have provided the first clues as to the factors that
govern the unique substrate specificities of some of these enzymes. In
the future these and other studies will facilitate prediction of the
fate of chemicals metabolised by sulfation. Variation in sulfation
capacity may be important in determining an individual's response to
xenobiotics, and there has been an explosion in information on
sulfotransferase polymorphisms and their functional consequences,
including the influence of SULT1A1 genotype on susceptibility to
colorectal and breast cancer. Finally, the first gene knockout
experiments with SULTs have recently been described, with the
generation of estrogen sulfotransferase deficient mice in which
reproductive capacity is compromised. Our improved understanding of
these enzymes will have significant benefits in such diverse areas as
drug design and development, cancer susceptibility, reproduction and
development.
PMID: 12439736
20. Transport of glutathione-conjugates in human erythrocytes
Sharma R, Awasthi S, Zimniak P, Awasthi YC.
Acta Biochim Pol. 2000;47(3):751-62.
http://www.actabp.pl/pdf/3_2000/751.pdf
The last step of detoxification of both endogenous and environmental
toxicants is typically a conjugation that produces a bulky hydrophilic
molecule. The excretion of such conjugates out of cells is of
sufficient biological importance to have led to the evolution of
ATP-driven export pumps for this purpose. The substrate specificity of
such transporters is broad, and in some cases it has been shown to
include not only anionic conjugates but also neutral or weakly cationic
drugs. In the present article, we review the molecular identity,
functional and structural characteristics of these pumps, mainly on the
example of human erythrocytes, and discuss their physiological role in
detoxification and in the multidrug resistance phenotype of cancer
cells.
PMID: 11310974
21. Metabolism of chemical carcinogens
Guengerich FP.
Carcinogenesis. 2000 Mar;21(3):345-51.
http://carcin.oxfordjournals.org/cgi/content/full/21/3/345
The transformation of chemicals is important in carcinogenesis, both in
bioactivation and detoxification. Major advances in the past 20 years
include appreciation of the migration of reactive electrophiles, the
ability of Phase II conjugating enzymes to activate chemicals,
understanding of the human enzymes, the realization that DNA
modification can result from endogenous chemicals, and the
demonstration that cancers can result from the metabolism of chemicals
to non-covalently bound products. Pathways of transformation in which
major insight was gained during the past 20 years include
nitropolycyclic hydrocarbons, polycyclic hydrocarbons and their diols,
vinyl halides and dihaloalkanes. Advances in analytical methods and
recombinant DNA technology contributed greatly to the study of
metabolism of chemical carcinogens. Major advances have been made in
the assignment of roles of individual enzymes in reactions. The
knowledge developed in this field has contributed to growth in the
areas of chemoprevention, molecular epidemiology and species
comparisons of risk. Some of the areas in which future development
relevant to carcinogen metabolism is expected involve pathways of
transformation of certain chemicals, regulation of genes coding for
many of the enzymes under consideration and genomics.
PMID: 10688854
22. The detoxification enzyme systems
Liska DJ.
Altern Med Rev. 1998 Jun;3(3):187-98.
http://www.thorne.com/media/detoxificationenzymes.pdf
The human body is exposed to a wide array of xenobiotics in one s
lifetime, from food components to environmental toxins to
pharmaceuticals, and has developed complex enzymatic mechanisms to
detoxify these substances. These mechanisms exhibit significant
individual variability, and are affected by environment, lifestyle, and
genetic influences. The scientific literature suggests an association
between impaired detoxification and certain diseases, including cancer,
Parkinson's disease, fibromyalgia, and chronic fatigue/immune
dysfunction syndrome. Data regarding these hepatic detoxification
enzyme systems and the body s mechanisms of regulating them suggests
the ability to efficiently detoxify and remove xenobiotics can affect
these and other chronic disease processes. This article reviews the
myriad detoxification enzyme systems, their regulatory mechanisms, and
the dietary, lifestyle, and genetic factors influencing their
activities, as well as laboratory tests available to assess their
functioning.
PMID: 9630736
23. Advances in mechanisms of activation and deactivation of environmental chemicals
Goldstein JA, Faletto MB.
Environ Health Perspect. 1993 Apr;100:169-76.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1519589&blobtype=pdf
Environmental chemicals are both activated and detoxified by phase I
and phase II enzymes. The principal enzymes involved in phase I
reactions are the cytochrome P-450s. The phase II enzymes include
hydrolase and the conjugative enzymes such as glucuronyltransferases,
glutathione transferases, N-acetyltransferase, and sulfotransferase.
Although other phase I and phase II enzymes exist, the present review
is limited to these enzymes. Once thought to be a single enzyme,
multiple cytochrome P-450 enzymes have been purified and characterized
from many different species across the evolutionary tree. The
application of molecular biology techniques to this field has
identified more than 150 cytochrome P-450 genes to date. At least 20-30
cytochrome P-450 enzymes appear to exist in each mammalian species, and
many polymorphisms in these enzymes are being identified. The
cytochrome P-450 enzymes can now be expressed in recombinant form using
cDNA expression systems. The phase II conjugative enzymes add a
hydrophilic moiety such as sulfate, glucuronide, or acetate to
compounds, which increases their water solubility and facilitates their
excretion. However, conjugates of a number of compounds also result in
more reactive electrophilic species, which appear to be the ultimate
carcinogens. Many of these phase II enzymes also represent families of
enzymes, and polymorphisms can affect the ability of these enzymes to
metabolize chemicals. Whenever possible, we have reviewed knowledge of
the human enzymes involved in particular pathways.
PMID: 8354165
24. The relevance of xenobiotic metabolism in the interindividual susceptibility to chemicals
Testai E.
Folia Histochem Cytobiol. 2001;39 Suppl 2:48-9.
Biotransformation enzymes may catalyze either detoxication or
bioactivation reactions; indeed, many xenobiotics exert their toxic
effects after metabolic activation to electrophilic chemicals,
interacting with nucleophilic sites on cellular macromolecules. On the
other hand, by increasing xenobiotic hydrophilicity, the
drug-metabolizing enzymes favors excretion of lipophilic chemicals, not
allowing their bioaccumulation up to toxic levels. The expression of
the enzymes of the drug-metabolizing system is modulated by genetic,
pathological, developmental, environmental and dietary factors. Genetic
polymorphism resulting in interindividual and interethnic variation in
xenobiotic metabolism is responsible for differences in the
susceptibility to chemical-induced toxicity and carcinogenicity,
allowing the identification of people at increased risk. Moreover,
differences in drug metabolism may correspond to variability in drug
response during pharmacological therapy, which can be manifest either
as adverse reactions or as a lack of benefit.
PMID: 11820624
25. ADHD: Genes and Environment
26. AD & ADHD: Mercury, Lead, Aluminum, and other Pollutants
27. Pediatric pharmacokinetic data: implications for environmental risk assessment for children
Ginsberg G et al.
Pediatrics. 2004 Apr;113(4 Suppl):973-83.
http://pediatrics.aappublications.org/cgi/content/full/113/4/S1/973
Pharmacology and toxicology share a common interest in pharmacokinetic
data, especially as it is available in pediatric populations. These
data have been critical to the clinical pharmacologist for many years
in designing age-specific dosing regimens. Now they are being used
increasingly by toxicologists to understand the ontogeny of physiologic
parameters that may affect the metabolism and clearance of
environmental toxicants. This article reviews a wide range of
physiologic and metabolic factors that are present in utero and in
early postnatal life and that can affect the internal dose of an
absorbed chemical and its metabolites. It also presents a child/adult
pharmacokinetic database that includes data for 45 therapeutic drugs
organized into specific children's age groupings and clearance
pathways. Analysis of these data suggests that substantial child/adult
differences in metabolism and clearance are likely for a variety of
drugs and environmental chemicals in the early postnatal period. These
results are also relevant to in utero exposures, where metabolic
systems are even more immature, but exposures are greatly modified by
the maternal system and placental metabolism. The implications of these
child/adult differences for assessing children's risks from
environmental toxicants is discussed with special focus on
physiologically based pharmacokinetic modeling strategies that could
simulate children's abilities to metabolize and eliminate chemicals at
various developmental stages.
PMID: 15060190
28. Human interindividual variability in susceptibility to airborne particles
Hattis D et al.
Risk Anal. 2001 Aug;21(4):585-99.
Part of the explanation for the persistent epidemiological findings of
associations between mortality and morbidity with relatively modest
ambient exposures to airborne particles may be that some people are
much more susceptible to particle-induced responses than others. This
study assembled a database of quantitative observations of
interindividual variability in pharmacokinetic and pharmacodynamic
parameters likely to affect particle response. The pharmacodynamic
responses studied included data drawn from epidemiologic studies of
doses of methacholine, flour dust, and other agents that induce acute
changes in lung function. In general, the amount of interindividual
variability in several of these pharmacodynamic response parameters was
greater than the variability in pharmacokinetic (breathing rate,
deposition, and clearance) parameters. Quantitatively the results
indicated that human interindividual variability of breathing rates and
major pharmacokinetic parameters-total deposition and tracheobronchial
clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to
geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58).
Deposition to the deep lung (alveolar region) appeared to be somewhat
more variable: Log(GSD) of about 0.3 (GSD of about 2). Among
pharmacodynamic parameters, changes in FEV1 in response to ozone and
metabisulfite (an agent that is said to act primarily on neural
receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4.
However, similar responses to methacholine, an agent that acts on
smooth muscle, seemed to have still more variability (0.4 to somewhat
over 1.0, depending on the type of population studied). Similarly high
values were suggested for particulate allergens. Central estimates of
this kind of variability, and the close correspondence of the data to
lognormal distributions, indicate that 99.9th percentile individuals
are likely to respond at doses that are 150 to 450-fold less than would
be needed in median individuals. It seems plausible that acute
responses with this amount of variability could form part of the
mechanistic basis for epidemiological observations of enhanced
mortality in relation to ambient exposures to fine particles.
PMID: 11726014
29. Distributions of individual susceptibility among humans for toxic
effects. How much protection does the traditional tenfold factor
provide for what fraction of which kinds of chemicals and effects?
Hattis D, Banati P, Goble R.
Ann N Y Acad Sci. 1999;895:286-316.
A significant data base has been assembled on human variability in
parameters representing a series of steps in the pathway from external
exposure to the production of biological responses: contact rate (e.g.,
breathing rates/body weight, fish consumption/body weight); uptake or
absorption (mg/kg)/intake or contact rate; general systemic
availability net of first pass elimination and dilution; systemic
elimination or half-life; active site availability/general systemic
availability; physiological parameter change/active site availability;
functional reserve capacity--change in baseline physiological parameter
needed to pass a criterion of abnormal function or exhibit a response.
This paper discusses the current results of analyzing these data to
derive estimates for distributions of human susceptibility to different
routes of exposure and types of adverse effects. The degree of
protection is tentatively evaluated by projecting the incidences of
effects that would be expected for a tenfold lowering of exposure from
a 5% incidence level if the population distribution of susceptibility
were truly log-normal out to the extreme tails, and if the populations,
chemicals, and responses that gave rise to the underlying data were
representative of the cases to which traditional uncertainty factor is
applied. The results indicate that, acting by itself, a tenfold
reduction in dose from a 5% effect level is associated with effect
incidences ranging from slightly less than one in ten thousand, for a
median chemical/response, to a few per thousand, for chemicals and
responses that have greater human interindividual variability than 19
out of 20 typical chemicals/responses. In practice, for many of the
cases where the traditional tenfold factor is applied, additional
protection is provided by other uncertainty factors. Nevertheless, the
results generate some reason for concern that current application of
traditional safety or uncertainty factor approaches may allow
appreciable incidences of responses in some cases.
PMID: 10676424
30. The economic impact of early life environmental tobacco smoke exposure: early intervention for developmental delay
Miller T et al.
Environ Health Perspect. 2006 Oct;114(10):1585-8.
http://www.ehponline.org/members/2006/9165/9165.html
BACKGROUND AND OBJECTIVES: Early-life exposure to environmental
tobacco smoke (ETS) can result in developmental delay as well as
childhood asthma and increased risk of cancer. The high cost of
childhood asthma related to ETS exposure has been widely recognized;
however, the economic impact of ETS-related developmental delay has
been less well understood. METHODS AND RESULTS: The Columbia Center for
Children's Environmental Health (CCCEH) has reported adverse effects of
prenatal ETS exposure on child development in a cohort of minority
women and children in New York City (odds ratio of developmental delay
= 2.36; 95% confidence interval 1.22-4.58). Using the environmentally
attributable fraction (EAF) approach, we estimated the annual cost of
one aspect of ETS-related developmental delay: Early Intervention
Services. The estimated cost of these services per year due to ETS
exposure is > Dollars 50 million per year for New York City Medicaid
births and Dollars 99 million per year for all New York City births.
CONCLUSION: The high annual cost of just one aspect of developmental
delay due to prenatal exposure to ETS provides further impetus for
increased prevention efforts such as educational programs to promote
smoke-free homes, additional cigarette taxes, and subsidizing of
smoking cessation programs.
PMID: 17035147
31. Assessing cumulative health risks from exposure to environmental mixtures - three fundamental questions
Sexton K, Hattis D.
Environ Health Perspect. 2007 May;115(5):825-32. Epub 2007 Jan 24.
http://www.ehponline.org/members/2006/9165/9165.html
Differential exposure to mixtures of environmental agents, including
biological, chemical, physical, and psychosocial stressors, can
contribute to increased vulnerability of human populations and ecologic
systems. Cumulative risk assessment is a tool for organizing and
analyzing information to evaluate the probability and seriousness of
harmful effects caused by either simultaneous and/or sequential
exposure to multiple environmental stressors. In this article we focus
on elucidating key challenges that must be addressed to determine
whether and to what degree differential exposure to environmental
mixtures contributes to increased vulnerability of exposed populations.
In particular, the emphasis is on examining three fundamental and
interrelated questions that must be addressed as part of the process to
assess cumulative risk: a) Which mixtures are most important from a
public health perspective? and b) What is the nature (i.e., duration,
frequency, timing) and magnitude (i.e., exposure concentration and
dose) of relevant cumulative exposures for the population of interest?
c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and
consequence (e.g., additive, less than additive, more than additive) of
the mixture's interactive effects on exposed populations? The focus is
primarily on human health effects from chemical mixtures, and the goal
is to reinforce the need for improved assessment of cumulative exposure
and better understanding of the biological mechanisms that determine
toxicologic interactions among mixture constituents.
PMID: 17520074
32. Pollutants and autism:
33. Autism, Pollution, and Nutrients: a Unifying Relationship: Commentary by Teresa Binstock
Additional topics will be added from time to time
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