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 CYP1A induction by polychlorinated biphenyls (PCBs) have only been determined in rodents and birds. This study describes the first development of such a SAR in a primate species by using hepatocyte cultures of cynomolgus monkey (Macaca fascicularis). Hepatocyte cultures of primate species might be a more suitable model for humans than those of rodents. For 20 PCBs, the in vitro induction of CYP1A activity was determined by measuring dealkylation of either methoxyresorufin or ethoxyresorufin. Selection of PCBs was based on multivariate physical-chemical characterization of all tetra- through heptachlorinated congeners. The non-ortho-substituted congeners were found to be the most potent inducers, followed by the mono-ortho-substituted PCBs. Multiple-ortho-substituted congeners, with more than five chlorine atoms, were inducers of CYP1A activity in monkey hepatocytes as well, with EC50 values approximately 10,000 times higher than 3,3',4,4',5 PeCB (PCB 126), the most potent congener. Using partial least-squares (PLS) modeling, predictions of CYP1A activity were established for all other tetra- to hepta-substituted congeners. Several congeners, which are abundant in the (a)biotic environment, were predicted to have CYP1A activity in cynomolgus monkey hepatocytes. Because induction of CYP1A activity is generally used as an early and sensitive biomarker for the Ah-receptor-mediated potential of a chemical, further studies are recommended to determine the possible risks of these multiple-ortho PCBs to humans.
Research Institute of Toxicology, Utrecht University, Utrecht, NL-3508 TD, The Netherlands.
A S
AS
van der Burght
P J
PJ
Clijsters
G J
GJ
Horbach
P L
PL
Andersson
M
M
Tysklind
M
M
van den Berg
D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis; D010088:Oxidoreductases / Q000096:biosynthesis*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1