Regulation of CYP4A expression by bezafibrate in primary culture of rat and human hepatocytes: interspecies difference and influence of N-acetylcysteine.
The effects of fibrates on cytochrome P450 4A (CYP4A) expression have not been clearly evaluated in human hepatocytes, human being reported as a non-responsive species. We have evaluated the effects of clofibrate, bezafibrate (BEZA), WY-14643, nafenopin and ciprofibrate at the concentration of 250 microM on CYP4A expression in primary cultures of rat and human hepatocytes. BEZA greatly induced mRNA expression in both species. Eight out of 10 human cultures responded to BEZA 250 microM. CYP4A-dependent activity was increased in rat, but not in human hepatocytes. The antioxidant N-acetylcysteine (Nac) enhanced the inducing effect of BEZA on mRNA expression, this potentialization being higher in human compared to rat hepatocytes. By contrast, Nac decreased the inducing effect of BEZA on CYP4A-dependent activity in rat and had either no effect or decreased the activity in BEZA-treated human hepatocytes. In conclusion, the cellular environment appears as an important parameter to take into account when studying CYP4A induction and could partly explain interspecies differences in the complex regulation of CYP4A expression.
Alvergnas
M
M
Laboratoire de Toxicologie Cellulaire, EA 4267, UFR des Sciences Médicales et Pharmaceutiques, 25030 Besançon cedex, France.
Richert
L
L
Blanchard
N
N
Abadie
C
C
Heyd
B
B
Mantion
G
G
Gallemann
D
D
Martin
H
H
D000111:Acetylcysteine / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D002995:Clofibric Acid; D042926:Cytochrome P-450 CYP4A; D000111:Acetylcysteine; D001629:Bezafibrate