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Titolo:
Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites
Autore:
Marill, J; Cresteil, T; Lanotte, M; Chabot, GG;
Indirizzi:
Univ Paris 07, Hop St Louis, Inst Univ Hematol, INSERM,U496,Ctr Hayem, F-75475 Paris 10, France Univ Paris 07 Paris France 10 M,U496,Ctr Hayem, F-75475 Paris 10, France Inst Gustave Roussy, CNRS, Unite Mixte Rech, Villejuif, France Inst Gustave Roussy Villejuif France nite Mixte Rech, Villejuif, France
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 6, volume: 58, anno: 2000,
pagine: 1341 - 1348
SICI:
0026-895X(200012)58:6<1341:IOHCPI>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE PROMYELOCYTIC LEUKEMIA; BREAST-CANCER CELLS; HUMAN-LIVER; BIOLOGICAL-ACTIVITY; INVITRO METABOLISM; EXPRESSION; DIFFERENTIATION; PROLIFERATION; INHIBITION; HAMSTER;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Chabot, GG Univ Paris 07, Hop St Louis, Inst Univ Hematol, INSERM,U496,CtrHayem, 1 Ave Claude Vellefaux, F-75475 Paris 10, France Univ Paris 07 1 Ave Claude Vellefaux Paris France 10 0, France
Citazione:
J. Marill et al., "Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites", MOLEC PHARM, 58(6), 2000, pp. 1341-1348

Abstract

Cytochrome P450 (P450)-dependent metabolism of all-trans-retinoic acid (atRA) is important for the expression of its biological activity. Because thehuman P450s involved in the formation of the principal atRA metabolites have been only partially identified, the purpose of this study was to identify the human P450s involved in atRA metabolism. The use of phenotyped human liver microsomes (n = 16) allowed the identification of the following P450s: 2B6, 2C8, 3A4/5, and 2A6 were involved in the formation of 4-OH-RA and 4-oxo-RA; 2B6, 2C8, and 2A6 correlated with the formation of 18-OH-RA; and 2A6, 2B6, and 3A4/5 activities correlated with 5,6-epoxy-RA formation (30-minincubation, 10 muM atRA, HPLC separation, UV detection 340 nm). The use of15 cDNA-expressed human P450s from lymphoblast microsomes, showed the formation of 4-OH-RA by CYP3A7> CYP3A5> CYP2C18> CYP2C8> CYP3A4> CYP2C9, whereas the 18-OH-RA formation involved CYPs 4A11> 3A7> 1A1> 2C9> 2C8> 3A5> 3A4>2C18. Kinetic studies identified 3A7 as the most active P450 in the formation of three of the metabolites: for 4-OH-retinoic acid, 3A7 showed a V-max/K-m of 127.7, followed by 3A5 (V-max/ K-m = 25.6), 2C8 (V-max/K-m = 24.5), 2C18 (V-max/K-m = 15.8), 3A4 (V-max/K-m = 5.7), 1A1 (V-max/K-m = 5.0), and 4A11 (V-max/K-m = 1.9); for 4-oxo-RA, 3A7 showed a V-max/K-m of 13.4, followed by a 10-fold lower activity for both 2C18 and 4A11 (V-max/K-m = 1.2); and for 18-OH-RA, 3A7 showed a V-max/K-m of 10.5 compared with a V-max/K-m of2.1 for 4A11 and 2.0 for 2C8. 5,6-Epoxy- RA was only detected at high substrate concentrations in this system (>10 muM), and P450s 2C8, 2C9, and 1A1 were the most active in its formation. The use of embryonic kidney cells (293) stably transfected with human P450 cDNA confirmed the major involvementof P450s 3A7, 1A1, and 2C8 in the oxidation of atRA, and to a lesser extent, 1A2, 2C9, and 3A4. In conclusion, several human P450s involved in atRA metabolism have been identified, the expression of which was shown to directatRA metabolism toward the formation of specific metabolites. The role of these human P450s in the biological and anticancer effects of atRA remains to be elucidated.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 00:55:01