Polybrominated biphenyl induction of cytochrome P450 mixed function oxidase activity in primary rat and human hepatocytes

Abstract

Polybrominated biphenyl (PBB) is an industrial chemical and environmental contaminant with known incidence of significant human exposure. PBB has been studied in laboratory animals and found to have significant toxicological effects as well as being a potent inducer of hepatic cytochrome P450 mixed function oxidase (MFO) activity. As part of our program to compare the response of laboratory animals and humans to industrial and environmental toxicants, we studied the effect of a major component of commercial PBB mixtures, 2,2′,4,4′,5,5′-hexabromobiphenyl (HBB), on MFO induction in primary cultures of human and rat hepatocytes. MFO induction was evaluated by measuring the deethylation of 7-ethoxycoumarin by intact hepatocytes. Rat hepatocytes were found to be highly susceptible to HBB induction of 7-ethoxycoumarin O-deethylase (ECOD) activity, with significant induction observed at the lowest concentration tested of 10 −8 M. Human hepatocytes were found to have a higher threshold for HBB induction of ECOD activity than rat hepatocytes. The lowest concentration of HBB required for ECOD induction observed for human hepatocytes was 10- to 1000-fold higher (10 −7, 10 −6, 10 −5 and 10 −5 M for the four human samples) than that found in rat hepatocytes. Future mechanistic investigation of this observed difference in sensitivity towards PBB between rat and human hepatocytes may aid the extrapolation of human health risk from toxicological data obtained from laboratory animals.