Pyridine and its metabolites have been shown in previous studies to induce cytochrome P4501A1 (CYP1A1) expression in vivo in the rat and in vitro in cultured human lung explants. In this study, we assessed the role of the metabolites in CYP1A1 induction by the parent compound. This was accomplished by comparing pyridine, 2-hydroxypyridine, 3-hydroxypyridine, pyridine N-oxide, and N-methylpyridinium in terms of the induction of CYP1A1 mRNA, CYP1A1 catalytic activity, and a xenobiotic response element-directed chloramphenicol acetyltransferase reporter gene, using HepG2 cells as the experimental system. We also assessed the effect of expression of the pyridine-metabolizing enzyme cytochrome P4502E1 on CYP1A1 induction by the parent pyridine. Only 2-hydroxypyridine significantly induced the CYP1A1 mRNA expression and CYP1A1-preferential activity ethoxyresorufin O-deethylase in wild-type HepG2 cells. Similarly, only 2-hydroxypyridine induced the expression of a xenobiotic response element-directed reporter gene in transfected HepG2 cells. Pyridine elevated CYP1A1 mRNA abundance 4.6-fold in HepG2 cells transfected with a human CYP2E1 expression vector relative to the abundance of the transcript in empty vector-transfected (control) HepG2 cells; the elevation was inhibited by the CYP2E1 inhibitor dimethyl sulfoxide. The results indicate that CYP1A1 induction by pyridine is mediated largely by metabolites, the formation of which may be catalyzed by CYP2E1.
Copyright 2002 Elsevier Science (USA).