Biotransformation of PCBs: Metabolic Pathways and Mechanisms

Abstract

Biotransformation of PCBs to hydroxylated metabolites by the microsomal cytochrome P-450 system is the critical event that determines the biological half-lives of these widespread environmental contaminants. The factors that determine the rate of biotransformation of PCBs are: the number of chlorines on the biphenyl nucleus, the position of these chlorines and the animal species. In general, as the number of chlorines increase and as the number of unsubstituted, adjacent carbon atoms decrease, the rate of cytochrome P-450 catalyzed hydroxylation of PCBs decreases. Evidence suggests that PCBs are hydroxylated via an arene-oxide intermediate, although other mechanisms may also be operative. The reactive arene oxides formed during biotransformation can bind covalently to tissue macromolecules and/or conjugate with glutathione. Derivatives of glutathione conjugates are major excretion products of PCBs as are glucuronides of the hydroxylated products. The species’ differences in the rate of metabolism of PCBs can be related, at least in part, to differences in the basal levels of particular isozymes of cytochrome P-450 present in liver. The dog, which eliminates PCBs more rapidly than other species, possesses higher levels of a constitutive isozyme of cytochrome P-450 with activity towards the slowly metabolized, bioaccumulated, 2,2′,4,4′,5,5′-hexachlorobiphenyl. Future studies will determine the factors that regulate the activity of this particular isozyme as well as determine its activity toward other PCBs.