DIFFERENTIAL-EFFECTS OF CIPROFIBRATE ON RENAL AND HEPATIC CYTOCHROME-P450 2E1 EXPRESSION

Since cytochrome P450 2E1 (CYP2E1) mRNA levels have been reported to b e increased during physiological states in which peroxisomes are incre ased, we examined the effects of the peroxisome proliferator, ciprofib rate (CIPRO), on renal and hepatic CYP2E1 expression, as wed as other enzymes associated with peroxisome proliferation, including CYP4A, CYP 2B, fatty acyl CoA oxidase (FACO), and peroxisomal thiolase (PT). Male rats were treated with CIPRO for 18, 48, or 120 hr. Northern blot or immunoblot analyses were used to determine mRNA or protein levels, res pectively, relative to levels in vehicle controls. CIPRO elevated rena l CYP2E1 and CYP4A mRNA levels similar to 3- to 4-fold at 18 hr, and t hese levels remained elevated to 120 hr. CIPRO progressively increased renal CYP2E1 and CYP4A protein levels, so that similar to 7-and 4-fol d increases, respectively, were observed at 120 hr of treatment. CIPRO treatment increased renal peroxisomal FACO mRNA levels similar to 2-f old and PT mRNA levels similar to 4- to 6-fold at all time points. In contrast to results observed in the kidney, hepatic CYP2E1 mRNA and pr otein levels were unchanged by CIPRO treatment. Hepatic CYP4A mRNA lev els were increased similar to 100-fold at all time points. Hepatic CYP 2B mRNA levels were elevated similar to 5-fold, but only at the 120-hr time point. Hepatic CYP4A and CYP2B protein levels were elevated in p roportion to the respective mRNA levels. Hepatic FACO mRNA levels were increased similar to 5-, 9-, and 20-fold, and hepatic PT mRNA levels were increased similar to 15-, 24-, and 39-fold, at 18, 48, and 120 hr , respectively. These results show that CIPRO-mediated, tissue-specifi c changes in CYP2E1 expression are not obligatorily associated with el evations in peroxisomal enzymes. (C) 1996 Academic Press, Inc.