Species-dependent Metabolism of Benzo[c]phenanthrene and Dibenzo[a, l]pyrene by Various CYP450 Isoforms

Abstract

The metabolism of benzo[c]phenanthrene (B[c]Ph) and dibenzo[a, l]-pyrene (DB[a, l]P) with various CYP isoforms including rat 1A1, 1A2, 2B1, 2E1, human 1A1, 1A2, 1B1, 2A6, 3A4, 2E1 and fish 1A expressed in Chinese hamster V79 cells has been compared. Major differences in the catalytic activities and in the regioselectivity of the eleven CYP isoforms with B[c]Ph and DB[a, l]P as substrates have been observed. There have been found substantially species-specific differences between homologous CYP isoforms at least when human, rat and fish are compared, which have to be taken into account when animal experiments are extrapolated to human. In particular, complementary catalytic activities of human CYP isoforms 1A1 and 1B1 could be demonstrated with B[c]Ph as substrate, i.e. CYP 1A1 is the major isoform involved in the formation of the proximate B[c]Ph 3,4-dihydrodiol metabolite, whereas its further oxidation to the ultimately carcinogenic fjord-region B[c]Ph-3,4-diol 1,2-epoxide metabolite is predominantly catalyzed by CYP 1B1.