GSTM1, GSTT1, and GSTP1 genotypes and the genotoxicity of hydroquinone in human lymphocytes.

Hydroquinone is a myelotoxin that is found in many foods and is also formed through the metabolism of benzene. Human exposure to benzene is associated with the development of myelodysplastic syndrome and acute myelogenous leukemia. Hydroquinone is genotoxic in several in vitro and in vivo test systems, inducing micronuclei (MN), sister-chromatid exchange (SCE), and chromosomal aberrations. Glutathione S-transferases (GSTs) are a superfamily of polymorphic enzymes involved in the conjugation of reactive chemical intermediates to soluble forms. These enzymes play a key role in the detoxification of endogenous and exogenous compounds, and the polymorphic genes GSTM1, GSTT1, and GSTP1 have been associated with the differential metabolism of several genotoxicants. In the present study, we have evaluated the effect of GSTM1, GSTT1, and GSTP1 polymorphisms on the frequency of MN and SCE induced by hydroquinone in human lymphocytes. Lymphocytes were obtained from 15 healthy non-smoking donors, and their GSTM1, GSTT1, and GSTP1 genotypes determined. Treatment of cultures of the lymphocytes with hydroquinone significantly increased the overall frequencies of MN and SCE (P<0.0001). Individuals with the GSTM1 null genotype had a significantly higher frequency of MN compared with GSTM1-present individuals (P=0.013); in contrast, the GSTM1 genotype had no effect on hydroquinone-induced SCE frequency. The other polymorphisms did not significantly affect the frequencies of MN or SCE. These results suggest that GSTM1 is involved in the metabolic fate of hydroquinone and that polymorphisms in GSTM1 could be related to inter-individual differences in DNA damage arising from the exposure to this compound.

Mechanisms of induction of chromosomal aberrations by hydroquinone in V79 cells.

Hydroquinone occurs naturally in bacteria and plants and it is also manufactured for commercial use. Human exposure to this compound can occur by environmental, occupational, dietary and cigarette smoke exposure and from exposure to benzene, which can be metabolized to this compound. However, the main source of exposure to this compound is dietary, since hydroquinone is a naturally occurring compound in many foods. Hydroquinone can be metabolized to benzoquinones, which are potent haematotoxic, genotoxic and carcinogenic compounds that can also induce the formation of radical species, predisposing cells to oxidative damage. In order to clarify the involvement of radical species in the genotoxicity of hydroquinone, the induction of chromosomal aberrations in V79 cells was studied along with the assessment of the production of hydroxyl radicals at different pH values (6.0, 7.4 and 8.0), as well as the effect of antioxidant enzymes [catalase and superoxide dismutase (SOD)] on the clastogenic effect of hydroquinone. The results obtained indicate that the clastogenic activity of hydroquinone is dependent on the pH, suggesting that deprotonation is a fundamental step leading to DNA lesions under the experimental conditions used. The addition of S9 mix, SOD or SOD and catalase significantly decreased the clastogenic activity, suggesting the involvement of superoxide anion and hydrogen peroxide in the genotoxicity of hydroquinone. However, other species generated in the auto-oxidation process of hydroquinone, such as the semiquinone radical or the quinone, also seem to play a role in its genotoxicity, since the addition of antioxidant enzymes (catalase and SOD) or S9 mix do not lead to a complete abolition of the observed genotoxic activity. These results suggest the existence of at least two mechanisms associated with the genotoxic activity of this compound.