Comparative influences of different PB-type and 3-MC-type polychlorinated biphenyl-induced phenotypes on cytocidal hepatotoxicity of bromobenzene and acetaminophen.

The influences of in vivo treatment with two pure PCB congeners, 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP) and 3,3',4,4'-tetrachlorobiphenyl (TCBP), on the lethal cytotoxicity of bromobenzene and acetaminophen were examined in short-term primary cultures of isolated rat hepatocytes. Lethal injury was measured by release of lactate dehydrogenase (LDH) into culture medium after 20 hr exposure to the hepatotoxins. The HCBP, a PB-type inducer of cytochrome P-450, resembled phenobarbitone (PB) in its ability to increase susceptibility of hepatocytes to bromobenzene (0.5 to 1.6 mM) and acetaminophen (1 to 16 mM). This induced sensitivity was consistently inhibited by SKF-525-A (10 microM) but not alpha-naphthoflavone (ANF, 10 microM) in culture. The 3,3',4,4'-TCPB, a 3-MC-type inducer of cytochrome P-450, resembled 3-methylcholanthrene (3-MC) in its inability to induce susceptibility to bromobenzene. TCBP and 3-MC each increased (20- to 30-fold) cytotoxicity of acetaminophen by a mechanism substantially inhibitable by ANF but not SKF-525-A. These results demonstrate that categorizing pure PCB isomers and congeners into groups according to their different induction capabilities is predictive for their ability to modulate acute hepatocellular necrosis by bromobenzene and acetaminophen.