Determination of genotoxicity using a chloroperoxidase-mediated model of PAH-DNA adduct formation.

Abstract

Enzymes from cytochrome P450 superfamily, which are components of monooxygenase systems, are thought to play a major role in carcinogenic activation. The physicochemical properties of PAH’s and the catalytic properties of cytochrome P450 suggest that PAH’s are generally activated by two major mechanisms: One-electron oxidation with formation of radical cations and monooxygenation (two-electron oxidation) to yield bay-region diol epoxides (Devanesan et al. 1992; Wellemans et al 1994). Hemoproteins such as peroxidases, cytochromes, and hemoglobin are able to catalyze PAH’s oxidation in vitro (Vazquez-Duhalt et al. 1994; Torres et al. 1995; Ortiz-Leon et al. 1995). The reaction products are mainly quinones and the mechanism involves free radical formation. Chloroperoxidase (CPO) from Caldaryomyces fumago, an enzyme with three different catalytic activities (halogenase, peroxidase and catalase), catalyzes phenol oxidation (Carmichael et al. 1985). On the other hand, chloroperoxidase shows close structural (Dawson 1988) and catalytic similarities with the cytochrome P450 (Sundaramoorthy et al. 1995). The similarities of both proteins could help to provide a better understanding of the biological activities and structure of cytochrome P450 in vivo. The primary activation of PAH’s via one-electron by cytochrome P450 could be similar to the PAH-DNA binding mediated by chloroperoxidase.