Carbamazepine induces multiple cytochrome P450 subfamilies in rats.
We compared the effect of three different doses (30, 60, and 100 mg/kg) of carbamazepine (CBZ) administered intraperitoneally for 1, 3, and 7 days on the activity and protein content of hepatic cytochrome P450 (CYP) subfamilies in Sprague-Dawley rats. After 3-day- and 7-day administration with CBZ, the total CYP content had increased in a dose-dependent fashion. Among six enzyme activities examined, only aniline hydroxylase activity remained unchanged after 7-day treatment with CBZ. Pentoxyresorufin O-deethylase activity showed the most significant increase and was induced up to 7 days in a time-dependent fashion. Pretreatment of rats with cycloheximide significantly suppressed the pentoxyresorufin O-deethylase induction by one dose of 100 mg/day CBZ. Immunoblot analysis showed a significant correlation between the protein content of each isoenzyme examined and its activity except CYP2E1 after 7-day treatment with CBZ. Similar results were obtained in the mRNA levels of CYP subfamilies. These results suggested that CBZ may induce multiple CYP subfamilies, except CYP2E1, and the activity and the protein content of CYP2B showed the greatest increase with increased CYP2B mRNA.
Tateishi
T
T
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Asoh
M
M
Nakura
H
H
Watanabe
M
M
Tanaka
M
M
Kumai
T
T
Kobayashi
S
S
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002220:Carbamazepine / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D015347:RNA Probes / Q000737:chemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D015347:RNA Probes; D012333:RNA, Messenger; D003609:Dactinomycin; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide