Structure-dependent induction of CYP1A by polychlorinated biphenyls in hepatocytes of cynomolgus monkeys (Macaca fascicularis)

Until now structure-activity relationships (SARs) for in vitro or in vivo C YP1A induction by polychlorinated biphenyls (PCBs) have only been determine d in rodents and birds. This study describes the first development of such a SAR in a primate species by using hepatocyte cultures of cynomolgus monke y (Macaca fascicularis). Hepatocyte cultures of primate species might be a more suitable model for humans than those of rodents. For 20 PCBs, the in v itro induction of CYP1A activity was determined by measuring dealkylation o f either methoxyresorufin or ethoxyresorufin. Selection of PCBs was based o n multivariate physical-chemical characterization of all tetra- through hep tachlorinated congeners. The non-ortho-substituted congeners were found to be the most potent inducers, followed by the mono-ortho-substituted PCBs. M ultiple-ortho-substituted congeners, with more than five chlorine atoms, we re inducers of CYP1A activity in monkey hepatocytes as well, with EC50 valu es approximately 10,000 times higher than 3,3',4,4',5 PeCB (PCB 126), the m ost potent congener. Using partial least-squares (PLS) modeling, prediction s of CYP1A activity were established for all other tetra- to hepta-substitu ted congeners. Several congeners, which are abundant in the (a)biotic envir onment, were predicted to have CYP1A activity in cynomolgus monkey hepatocy tes. Because induction of CYP1A activity is generally used as an early and sensitive biomarker for the Ah-receptor-mediated potential of a chemical, f urther studies are recommended to determine the possible risks of these mul tiple-ortho PCBs to humans. (C) 1999 Academic Press.