Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism.
A form of human hepatic microsomal cytochrome P-450 (P450hA7) with subunit Mr 50,400 has been purified from an epileptic who had been receiving long-term treatment with anticonvulsant drugs. P450hA7 metabolized the immunosuppressant drug cyclosporin A and the dihydropyridine calcium channel antagonist nifedipine, but did not metabolize a similar dihydropyridine drug, nicardipine, nor a series of alkoxyresorufin model substrates. The hepatic microsomal concentration of P450hA7 was higher in five individuals who had been receiving long-term anticonvulsant treatment than in any of 21 individuals who had not been similarly treated. The mean P450hA7 concentration in the treated individuals was 5-fold higher than the mean concentration in the untreated individuals. It is concluded that P450hA7 is a member of the cytochrome P450III family which is induced by anticonvulsant drugs in man.
Shaw
P M
PM
Department of Pharmacology, University of Aberdeen, U.K.
Barnes
T S
TS
Cameron
D
D
Engeset
J
J
Melvin
W T
WT
Omar
G
G
Petrie
J C
JC
Rush
W R
WR
Snyder
C P
CP
Whiting
P H
PH
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015153:Blotting, Western; D003429:Cross Reactions; D003524:Cyclosporins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007158:Immunologic Techniques; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010449:Peptide Mapping; D051381:Rats; D013057:Spectrum Analysis; D013379:Substrate Specificity
D000927:Anticonvulsants; D003524:Cyclosporins; D003577:Cytochrome P-450 Enzyme System