Male-specific induction of CYP3A2 in rats by zolmitriptan.
We report here a novel observation that zolmitriptan induced CYP3A2 in male but not female rats. As part of our research programme to evaluate sex differences in the response to zolmitriptan, we studied the effects of zolmitriptan on CYP3A activity, protein and gene expression in male and female rats. Zolmitriptan was found to induce CYP3A activity, measured as testosterone and diazepam metabolism in-vitro, as well as midazolam pharmacokinetics in-vivo, in male but not female rats. The sex difference in response to zolmitriptan was further evaluated by analysis of CYP3A1/2 mRNA levels using real-time PCR, and CYP3A1/2 protein levels using immunoblotting. Zolmitriptan preferentially induced CYP3A2 in male but not female rats. No obvious effects on CYP3A1 were observed at any dose in either sex. Thus, we concluded that the observed sex-dependent induction of CYP3A by zolmitriptan was largely due to induction of CYP3A2 in male rats.
Yu
Lushan
L
Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Lu
Sijie
S
Zhao
Naping
N
Ni
Shaoqing
S
Yao
Tongwei
T
Zeng
Su
S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003975:Diazepam / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects*; D008874:Midazolam / Q000378:metabolism; D023303:Oxazolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology*
D008565:Membrane Proteins; D023303:Oxazolidinones; D012333:RNA, Messenger; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; D013739:Testosterone; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D003975:Diazepam; D008874:Midazolam