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Titolo:
Oxidation mechanism of 7-hydroxy-Delta(8)-tetrahydrocannabinol and 8-hydroxy-Delta(9)-tetrahydrocannabinol to the corresponding ketones by CYP3A11
Autore:
Matsunaga, T; Tanaka, H; Higuchi, S; Shibayama, K; Kishi, N; Watanabe, K; Yamamoto, I;
Indirizzi:
Hokuriku Univ, Fac Pharmaceut Sci, Dept Hyg Chem, Kanazawa, Ishikawa 9201181, Japan Hokuriku Univ Kanazawa Ishikawa Japan 9201181 wa, Ishikawa 9201181, Japan
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 11, volume: 29, anno: 2001,
pagine: 1485 - 1491
SICI:
0090-9556(200111)29:11<1485:OMO7A8>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
MOUSE HEPATIC MICROSOMES; LIVER-MICROSOMES; OXYGENATION MECHANISM; ENZYMATIC OXIDATION; CARBOXYLIC-ACID; GUINEA-PIG; CYTOCHROME-P-450; PURIFICATION; ALDEHYDE; 7-OXO-DELTA(8)-TETRAHYDROCANNABINOL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Yamamoto, I Hokuriku Univ, Fac Pharmaceut Sci, Dept Hyg Chem, Kanazawa, Ishikawa 9201181, Japan Hokuriku Univ Kanazawa Ishikawa Japan 9201181 9201181, Japan
Citazione:
T. Matsunaga et al., "Oxidation mechanism of 7-hydroxy-Delta(8)-tetrahydrocannabinol and 8-hydroxy-Delta(9)-tetrahydrocannabinol to the corresponding ketones by CYP3A11", DRUG META D, 29(11), 2001, pp. 1485-1491

Abstract

A cDNA isolated from a C57BL/6 mouse liver cDNA library had the identical nucleotide sequence in coding region with the mouse CYP3A11, and the NH2-terminal sequence was also identical to that of cytochrome P450 (P450) MDX-B,a microsomal alcohol oxygenase. The COS-7 cells transfected with the CYP3A11 expression vector formed 7-oxo-Delta (8)-tetrahydrocannabinol (7-oxo-Delta (8)-THC) from 7 alpha- and 7 beta -hydroxy-Delta (8)-THC. An immunologically related protein with P450 MDX-B was expressed in the COS-7 cell microsomes. The cell microsomes expressed CYP3A11; COS-3A11 catalyzed the oxidation of 7-hydroxy-Delta (8)-THC and 8-hydroxy-Delta (9)-THC to 7-oxo-Delta (8)-THC and 8-oxo-Delta (9)-THC, respectively, in a reconstituted system. O-18 derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7 alpha -hydroxy-Delta (8)-THC and 8 beta -hydroxy-Delta (9)-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7 beta -hydroxy-Delta (8)-THC and 8 alpha -hydroxy-Delta (9)-THC wasnegligible. O-18, however, was not incorporated into 7-oxo-Delta (8)-THC formed from 7 alpha -hydroxy-Delta (8)-THC by using cumene hydroperoxide instead of NADPH under O-18(2). When O-18-labeled 7 alpha -hydroxy-Delta (8)-THC and 8 beta -hydroxy-Delta (9)-THC were incubated with above enzymes under air, about 30% of the ketones formed released O-18 from a hydroxy group at the 7 and 8 positions in the course of the oxidation. These results suggest that 7 alpha -hydroxy-Delta (8)-THC and 8 beta -hydroxy-Delta (9)-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7 beta -Hydroxy-Delta (8)-THC and 8 alpha -hydroxy-Delta (9)-THC may be also converted to the ketones through a stereoselective dehydration of an enzyme-bound gem-diol rather than through a direct hydrogen extraction as a peroxy form of the enzyme.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 07:16:25