Studies on PCB toxicity involving 2C subfamily cytochrome P450

It has been demonstrated that PCB metabolism is mainly catalyzed by 1A and 2B subfamily cytochrome P450s, CYP 1A1/2 and CYP 2B1/2. These studies were conducted mostly with hepatic enzymes in rodents. The 1A and 2B subfamily P450s are constitutively expressed little, but markedly induced by xenobiotics such as 3-methylcholanthrene and phenobarbital in rodents. On the other hand, the recent studies showed that cytochrome P450s in human liver are remarkably different from isoform of rodents in constitution and enzyme activities. In the present study, we first tried to metabolize some PCBs with 2C subfamily cytochrome P450 (CYP2C) purified from dog liver microsomes. The data suggested that CYP2C may not be involved in PCB metabolism. Since CYP2C is the same most abundant enzyme as 3A subfamily P450 in human liver and plays a major role for metabolism of many drugs used clinically, and may also play an important role for metabolism of some steroid hormones, we further studied the inhibition of CYP2C-catalyzed steroid metabolism by typical PCB congeners. CYP2C-mediated steroid metabolism is greatly inhibited by 2,4,5,2',4',5'-hexachlorobiphenyl, but not by 3,4,5,3',4'-pentachlorobiphenyl. On the contrary, 3,4,5,3',4'-pentachlorobiphenyl markedly suppressed CYP2C expression in the dog liver. These results suggest that residual PCBs may affect the current situation of steroid hormones in Yusho patients, and may cause PCB-drug interactions.