Differential effects of ciprofibrate on renal and hepatic cytochrome P450 2E1 expression.
Since cytochrome P450 2E1 (CYP2E1) mRNA levels have been reported to be increased during physiological states in which peroxisomes are increased, we examined the effects of the peroxisome proliferator, ciprofibrate (CIPRO), on renal and hepatic CYP2E1 expression, as well as other enzymes associated with peroxisome proliferation, including CYP4A, CYP2B, 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, respectively, relative to levels in vehicle controls. CIPRO elevated renal CYP2E1 and CYP4A mRNA levels approximately 3- to 4-fold at 18 hr, and these levels remained elevated to 120 hr. CIPRO progressively increased renal CYP2E1 and CYP4A protein levels, so that approximately 7- and 4-fold increases, respectively, were observed at 120 hr of treatment. CIPRO treatment increased renal peroxisomal FACO mRNA levels approximately 2-fold and PT mRNA levels approximately 4- to 6-fold at all time points. In contrast to results observed in the kidney, hepatic CYP2E1 mRNA and protein levels were unchanged by CIPRO treatment. Hepatic CYP4A mRNA levels were increased approximately 100-fold at all time points. Hepatic CYP2B mRNA levels were elevated approximately 5-fold, but only at the 120-hr time point. Hepatic CYP4A and CYP2B protein levels were elevated in proportion to the respective mRNA levels. Hepatic FACO mRNA levels were increased approximately 5-, 9-, and 20-fold, and hepatic PT mRNA levels were increased approximately 15-, 24-, and 39-fold, at 18, 48, and 120 hr, respectively. These results show that CIPRO-mediated, tissue-specific changes in CYP2E1 expression are not obligatorily associated with elevations in peroxisomal enzymes.
Zangar
R C
RC
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Woodcroft
K J
KJ
Novak
R F
RF
D000818:Animals; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D058607:Fibric Acids; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A; C019304:ciprofibrate