Identification of rat and human cytochrome P450 forms involved in the metabolism of the thromboxane A2 receptor antagonist (+)-S-145.

Article Details

Citation

Copy to clipboard

Yamaguchi Y, Kirita S, Baba T, Aoyama J, Touchi A, Tukey RH, Guengerich FP, Matsubara T

Identification of rat and human cytochrome P450 forms involved in the metabolism of the thromboxane A2 receptor antagonist (+)-S-145.

Drug Metab Dispos. 1997 Jan;25(1):75-80.

PubMed ID

9010633 [ View in PubMed

]

Abstract

(+)-S-145 [5-(+)-(Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-heptenoic acid] and its beta-oxidized metabolites [two [bisnor or dihydro (DH)-bisnor] or four (tetranor) carbon-shortened products at the carboxyl side chain] are hydroxylated at the C-5 or C-6 position of the bicyclo ring by microsomal monooxygenases. We investigated the oxidative metabolism of (+)-S-145 and its beta-oxidized metabolites with liver microsomes from rats and humans to identify which cytochrome P450 (P450) forms are involved in these reactions. In rats, phenobarbital or dexamethasone treatment significantly increased 5- and 6-hydroxylation activities toward (+)-S-145 and its beta-oxidized metabolites, suggesting the involvement of P4503A forms. Immunoinhibition studies suggested that P4503A2 was mainly responsible for the 5-hydroxylation of (+)-S-145, bisnor, and DH-bisnor and the 6-hydroxylation of bisnor and tetranor. Furthermore, P4502C6, a phenobarbital-inducible 2C form in the rat, was involved in the 6-hydroxylation of (+)-S-145, bisnor, and DH-bisnor. P4502C11, the major constitutive form (male rats), was partly involved in the 5-hydroxylation of DH-bisnor and the 6-hydroxylation of bisnor and DH-bisnor. Reconstitution studies with purified human enzymes and immunoinhibition studies suggest that P4503A4 is primarily involved in the 5-hydroxylation of (+)-S-145 and bisnor and the 6-hydroxylation of tetranor; P4502C9/10 mainly catalyzed the 5-hydroxylation of tetranor and the 6-hydroxylation of (+)-S-145. Results of the present study indicated that the same subfamily P450 forms are responsible for the oxidative metabolism of (+)-S-145 in rats and humans. P4503A enzymes were shown to be involved in the formation of 6-hydroxy tetranor, the main metabolite of S-1452 in vivo.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dexamethasone	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details
Dexamethasone acetate	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details