Biological indicators of genotoxic risk and metabolic polymorphisms.
International scientific publications on the influence of metabolic genotypes on biological indicators of genotoxic risk in environmental or occupational exposure are reviewed. Biomarkers of exposure (substance or its metabolites in biological fluids, urinary mutagenicity, protein and DNA adducts) and of effects (chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (Mn), COMET assay, HPRT mutants) have been evaluated according to different genotypes (or phenotypes) of several activating/detoxifying metabolic activities. In less than half the studies (43 out of 95), the influence of genotype on the examined biological indicator was found, of which four report poorly reliable results (i.e., with scarce biological plausibility, because of the inconsistency of modulated effect with the type of enzymatic activity expressed). As regards urinary metabolites, the excretion of mercapturic acids (MA) is greater in subjects with high GST activity, that of 1-pyrenol and other PAH metabolites turns out to be significantly influenced by genotypes CYP1A1 or GSTM1 null, and that of exposure indicators to aromatic amines (AA) (acetylated and non-acetylated metabolites) is modulated by NAT2. In benzene exposure, preliminary results suggest an increase in urinary t, t-muconic acid (t,t-MA) in subjects with some genotypes. On urinary mutagenicity of PAH-exposed subjects, the effects of genotype GSTM1 null, alone or combined with NAT2 slow are reported. When DNA adduct levels are clearly increased in PAH-exposed group (18 out of 22), 7 out of 18 studies report the influence of GSTM1 null on this biomarker, and of the five studies which also examined genotype CYP1A1, four report the influence of genotype CYP1A1, alone or in combination with GSTM1 null. A total of 25 out of 41 publications (61%) evaluating the influence of metabolic polymorphisms on biomarkers of effect (cytogenetic markers, COMET assay, HPRT mutants) do not record any increase in the indicator due to exposure to the genotoxic agents studied, confirming the scarce sensitivity of these indicators (mainly HPRT mutants, Mn, COMET assay) for assessing environmental or occupational exposure to genotoxic substances. Concluding, in determining urinary metabolites for monitoring exposure to genotoxic substances, there is sufficient evidence that genetically-based metabolic polymorphisms must be taken into account in the future. The unfavourable association for the activating/detoxifying metabolism of PAH is also confirmed as a risk factor due to the formation of PAH-DNA adducts. The clearly protective role played by GSTT1 on DEB (and/or related compound)-induced sister chromatid exchanges (SCEs) should be noted. The modulating effects of genotypes on protein adduct levels in environmental and occupational exposure have not yet been documented, and most studies on the influence of genotype on biological indicators of early genotoxic effects report negative results.
Pavanello
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Dipartimento di Medicina Ambientale e Sanita' Pubblica, Universita' di Padova, Via Giustiniani 2, 35128, Padova, Italy.
Clonfero
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D000818:Animals; D015415:Biomarkers; D001711:Biotransformation / Q000235:genetics*; D001826:Body Fluids / Q000737:chemistry; D002273:Carcinogens / Q000009:adverse effects / Q000493:pharmacokinetics; D002869:Chromosome Aberrations; D020552:Comet Assay; D018736:DNA Adducts; D004249:DNA Damage; D004781:Environmental Exposure; D004798:Enzymes / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008658:Inactivation, Metabolic / Q000235:genetics; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000009:adverse effects / Q000493:pharmacokinetics; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D011506:Proteins / Q000187:drug effects; D012306:Risk; D012854:Sister Chromatid Exchange / Q000187:drug effects
D015415:Biomarkers; D002273:Carcinogens; D018736:DNA Adducts; D004798:Enzymes; D009153:Mutagens; D011506:Proteins; D007041:Hypoxanthine Phosphoribosyltransferase