The hydroxylation, dechlorination, and glucuronidation of 4,4′-dichlorobiphenyl (4-DCB) by human hepatic microsomes

Abstract

Since chlorine placement and the degree of chlorination of the biphenyl nucleus play an important role in the metabolism and ultimate elimination of polychlorinated biphenyls (PCBs), we have studied the metabolism of 4,4′-dichlorobiphenyl (4-DCB) by human hepatic musomes. This low molecular weight PCB congener is substituted at the preferred site of metabolism (para-position). 4-DCB was metabolized by human musomes with a K m of 0.43 μm and a V max of 1.2 pmoles/mg musomal protein/min. Six metabolites were identified: 4,4′-dichloro-3,3′-biphenyldiol, 4′-chloro-3-biphenylol, 4′-chloro-4-biphenylol, 4,4′-dichloro-2-biphenylol, 4,4′-dichloro-3-biphenylol (most abundant), and 3,4′-dichloro-4-biphenylol. [ 4C]-4-DCB equivalents were found to covalently bind to musomal protein. Addition of a 1 mM concentration of reduced glutathione decreased the degree of covalent binding. These data suggest that human musomes metabolize this PCB through an arene oxide and that an “NIH shift” occurs. When UDPGA was added to the incubation, human musomal glucuronosyltransferase catalyzed the formation of the glucuronide of the major metabolite, 4,4′-dichloro-3-biphenylol. These and previous in vitro results show that the biotransformation of PCBs by humans is governed by the same principles established for the in vivo biotransformation of PCBs by the rat, mouse and monkey. That is, PCBs without two adjacent unsubstituted carbon atoms are poorly metabolized and that an unsubstituted para-position facilitates metabolism.