Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4'-hydroxylation in human liver.

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Leemann T, Transon C, Dayer P

Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4'-hydroxylation in human liver.

Life Sci. 1993;52(1):29-34.

PubMed ID

8417277 [ View in PubMed

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Abstract

The nature of the enzyme(s) catalyzing the major metabolic pathway of diclofenac, 4'-hydroxylation, was investigated in human liver microsomes. Inhibition studies were performed with tolbutamide and sulfaphenazole (respectively the prototype substrate and a selective inhibitor of cytochrome P450TB--CYP2C subfamily), and with phenytoin and (+/-)-warfarin, other proposed substrates of P450TB. Diclofenac 4'-hydroxylation displayed single enzyme Michaelis-Menten kinetics and was similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6), with a Km of 5.6 +/- 1.5 microM (mean +/- sd) and a Vmax of 60.6 +/- 23.5 nmol/mgP/h. Inhibition by tolbutamide, sulfaphenazole, phenytoin and (+/-)-warfarin was comparable in all livers, with values predicted from their Km or Ki for cytochrome P450TB determined in separate studies and a competitive inhibition model. Sulfaphenazole competitively inhibited diclofenac 4'-hydroxylation (Ki = 0.11 +/- 0.08 microM, n = 3). Diclofenac 4'-hydroxylation is predominantly catalyzed by a cytochrome P450 isozyme of the CYP2C subfamily, most likely CYP2C9. This particular isozyme therefore appears to be responsible for the oxidation of polar acidic substances such as non-steroidal anti-inflammatory drugs from different chemical classes. It also constitutes a common site for drug interactions involving these compounds, as well as tolbutamide, phenytoin and warfarin.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Diclofenac	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate	Details