RT Journal Article
SR Electronic
T1 IDENTIFICATION OF RAT AND HUMAN CYTOCHROME P450 FORMS INVOLVED IN THE METABOLISM OF THE THROMBOXANE A<sub>2</sub> RECEPTOR ANTAGONIST (+)-<em>S</em>-145
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 75
OP 80
VO 25
IS 1
A1 Yoshitaka Yamaguchi
A1 Shirou Kirita
A1 Takahiko Baba
A1 Junko Aoyama
A1 Akira Touchi
A1 Robert H. Tukey
A1 F. Peter Guengerich
A1 Takashi Matsubara
YR 1997
UL http://dmd.aspetjournals.org/content/25/1/75.abstract
AB (+)-S-145 {5-(+)-(Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-heptenoic acid} and its β-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 β-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 β-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. The American Society for Pharmacology and Experimental Therapeutics