Coordinate up-regulation of CYP1A1 and heme oxygenase-1 (HO-1) expression and modulation of delta-aminolevulinic acid synthase and tryptophan pyrrolase activities in pyridine-treated rats

To determine the changes in heme metabolism associated with induction of cy tochrome P450 expression by pyridine, we compared the time course of CYP1A expression with the time course of (i) expression of heme oxygenase-l (HO-1 ) (EC 1.14.99.3), (ii) activity of delta-aminolevulinic acid synthetase (AL AS) (EC 2.3.1.37), and (iii) heme saturation of tryptophan pyrrolase (TPO) (EC 1.13.11.11) in tissues of rats administered a single 100 or 150 mg/kg i .p. dose of pyridine. Both mRNA and protein of HO-1 and CYP1A1 were induced in the liver, kidney, and lung, with the induction of HO-1 mRNA preceding and paralleling that of CYP1Al mRNA in the liver and lung but not kidney. I nduction of CYP1A1 mRNA expression peaked within 9-12 hr and returned to co ntrol levels by 24 hr in all tissues examined, whereas induction of HO-1 mR NA expression was sustained for 48 hr in the lung and liver. in contrast to the transient up-regulation of CYP1A1 mRNA, increased microsomal CYP1A1 pr otein was sustained in all three tissues. Similar to the induction of HO-1 expression, lipid peroxidation was stimulated by pyridine treatment in the kidney, lung, and liver, but with the stimulation bring mare persistent in the liver and lung than in the kidney. Increased hepatic CYP1A1 or CYP1A2 a ctivity was preceded by increased activities of HO-1 and ALAS. Pyridine tre atment negatively modulated heme saturation of hepatic TPO. The findings in dicate that pyridine stimulates the synthesis, utilization, and degradation of heme in a coordinate manner, and suggest, that these alterations in hem e metabolism may contribute to CYP1A1 induction by pyridine. (C) 1999 Elsev ier Science Inc.