Biological indicators of genotoxic risk and metabolic polymorphisms
Section snippets
Biological indicators of genotoxic risk
In 1988 biological indicators of genotoxic risk were the subject of a Consensus Report of the European Community [1]. On that occasion, techniques of biological monitoring to reveal exposure or the biological effects of genotoxic substances were summarised.
Biological indicators of genotoxic risk are subdivided into indicators of internal dose, biologically effective dose, and early biological effect. According to this classification, it is therefore possible to identify a biological indicator
Genetic polymorphisms
In studies dealing with the biomonitoring of genotoxic risk, many genetic polymorphisms of enzymes involved in the metabolism of xenobiotics have been examined: ALDH2 (aldehyde dehydrogenase 2), CYP1A1, CYP1A2, CYP2C, CYP2D6 (P450 cytochromes), EPHX (epoxidohydrolase), GSTM1, GSTP1, GSTT1 (glutathione S-transferase), NAT2 (N-acetyltransferase), NQO1 (NAD(P)H quinone oxidoreductase) and PON1 (paraoxonase). The characteristics of the various polymorphisms and their related biological activities
Substances and their metabolites in biological fluids
The first report of the influence of GST polymorphism in the excretion of mercapturic acids (MA) goes back to 1991, and concerned occupational exposure to 1,3-dichloropropene (DCP), a fumigant, classified by the IARC in group 2B (probable carcinogen). In exposure to DCP, the detoxifying activity of GSTM1 modulates the excretion of the two MA of DCP: exposure being equal, subjects with isoenzyme M1 have higher values [35]. However, in the study of Hayes et al. [36] detoxifying genotypes GSTM1
Urinary mutagens
Only a few studies have assessed the influence of metabolic polymorphisms on urinary mutagenic activity in subjects exposed occupationally or environmentally to genotoxins. Sinués et al. [53] examined such activity at the end of a working week in a textile industry where workers were possibly exposed to dyes based on AA. They found direct increased mutagenic activity in the presence of β-glucoronidase in exposed subjects with respect to controls and in slow-acetylator exposed subjects with
Protein adducts
Studies on protein adduct levels mainly deal with exposure to PAHs, AA, ethylene oxide (EtO) or similar compounds.
Santella et al. [56] determined PAH/albumin adducts (competitive ELISA assay) in psoriatic patients treated with coal tar-based creams. Values in patients were similar to those of controls, and no effect of genotype GSTM1 was found in the absence of any increase in the indicator. The negative influence of genotype GSTM1 on PAH/albumin adducts in environmentally exposed subjects is
SCEs
Hallier et al. in 1993 [66] were the first to report polymorphisms of glutathione transferase in erythrocytes (conjugating and non-conjugating towards methyl bromide), which strongly influence the in vitro formation of SCEs after exposure to methyl bromide, EtO and dichloromethane.
SCEs induced in vitro by diepoxybutane (DEB), a metabolite of 1,3-butadiene, are greater in subjects with GSTT1 null genotype but not with GSTM1 null [85]. Wiencke et al. [86], independently, demonstrated that
CAs and Mn
No influence of genotype GSTM1 has been found on CA frequency in environmental studies [40], [42], [78] or in workers exposed to pesticides [96]. Two studies deal with workers in plants producing 1,3-butadiene exposed to low concentrations (<1 ppm). Gaps excluded, CAs have been found more frequently in workers lacking GSTT1 [62]. Another similar work reports increased CA frequency in GSTM1 active exposed subjects [90]. In a study on exposure to urban air, bus drivers, mostly GSTM1 null and NAT2
Conclusive considerations
Table 2, Table 3, Table 4, Table 5, Table 6, Table 7 summarise results of 95 studies published until now on the influence of metabolic genotype on biological indicators of genotoxic risk (urinary metabolites and mutagens, protein and DNA adducts, SCEs, Mn, CAs, COMET assay and HPRT) in occupational or environmental exposure. The tables list both the genotypes and their possible effects on indicators, and the effect of exposure alone on indicators. In many studies, the effect of exposure is not
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