Comparative induction of CYP1A1 expression by pyridine and its metabolites

We compared pyridine and five of its metabolites in terms of (i) in vivo in duction of CYP1A1 expression in the lung, kidney, and liver in the rat and (ii) in vitro binding to, and activation of, the aryl hydrocarbon receptor (AhR) in cytosol from rat liver or Hepa1c1c7 cells. Following a single 2.5 mmol/kg ip dose of either pyridine, 2-hydroxpyridine, 3-hydroxypyridine, 4- hydroxypyridine, N-methylpyridinium, or pyridine N-oxide, CYP1A1 activity ( ethoxyresorufin O-deethylase), protein level (as determined by Western blot ting), and mRNA level (as determined by Northern blotting) were induced by pyridine, N-methylpyridinium, and pyridine N-oxide in the lung, kidney, and liver. The induction by N-methylpyridinium or pyridine N-oxide was compara ble to or greater than that by pyridine in some tissues. 2-Hydroxypyridine and 3-hydroxypyridine caused tissue-specific induction or repression of CYP 1A1, whereas 4-hydroxypyridine had no effect on the expression of the enzym e. Pyridine and its metabolites elicited weak activation of the aryl hydroc arbon receptor in a gel retardation assay in cytosol from rat liver but not Hepa 1c1c7 cells. However, the receptor activation did not parallel the in vivo CYP1A1 induction by the pyridine compounds, none of which inhibited b inding of [H-3]2,3,7,8-tetrachlorodibenzo-p-dioxin to AhR in a competitive assay in rat liver cytosol, The findings are consistent with a pole of pyri dine metabolites in CYP1A1 induction by pyridine but do not clearly identif y the role of aryl hydrocarbon receptor in the induction mechanism. (C) 200 0 Academic Press.