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Titolo:
THE EFFECTS OF CYTOCHROME B(5), NADPH-P450 REDUCTASE, AND LIPID ON THE RATE OF 6-BETA-HYDROXYLATION OF TESTOSTERONE AS CATALYZED BY A HUMANP450 3A4 FUSION PROTEIN
Autore:
SHET MS; FAULKNER KM; HOLMANS PL; FISHER CW; ESTABROOK RW;
Indirizzi:
UNIV TEXAS,SW MED CTR,DEPT BIOCHEM,5323 HARRY HINES BLVD DALLAS TX 75235 UNIV TEXAS,SW MED CTR,DEPT BIOCHEM DALLAS TX 75235
Titolo Testata:
Archives of biochemistry and biophysics
fascicolo: 2, volume: 318, anno: 1995,
pagine: 314 - 321
SICI:
0003-9861(1995)318:2<314:TEOCBN>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
LIVER MICROSOMAL CYTOCHROME-P-450; FUNCTION OXIDATION REACTIONS; HYDROGEN-PEROXIDE; NADPH-CYTOCHROME-P450 REDUCTASE; ELECTROSTATIC INTERACTIONS; DRUG-METABOLISM; XYLENOL ORANGE; HYDROPEROXIDE; INHIBITORS; MECHANISM;
Keywords:
STEROID HYDROXYLATION; HYDROGEN PEROXIDE FORMATION; OXY-P450; NADPH OXIDATION; CYTOCHROME P450 3A4; DIOLEOYLPHOSPHATIDYLCHOLINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
39
Recensione:
Indirizzi per estratti:
Citazione:
M.S. Shet et al., "THE EFFECTS OF CYTOCHROME B(5), NADPH-P450 REDUCTASE, AND LIPID ON THE RATE OF 6-BETA-HYDROXYLATION OF TESTOSTERONE AS CATALYZED BY A HUMANP450 3A4 FUSION PROTEIN", Archives of biochemistry and biophysics, 318(2), 1995, pp. 314-321

Abstract

The recombinant fusion protein containing the heme domain of human P450 3A4 and the flavin domains of rat NADPH-cytochrome P450 (P450) reductase (rF450[mHum3A4/mRat0R]L1) requires both phospholipid and detergent as well as cytochrome bs (b(5)) for the NADPH-dependent catalysis of the 6 beta-hydroxylation of testosterone. NADPH oxidation results inthe formation of hydrogen peroxide in the presence or absence of phospholipid and detergent. NADPH oxidation and hydrogen peroxide formation are inhibited by the addition of b(5) and stimulated greater than 3-fold by the addition of testosterone. Marked differences in the ability of various phospholipids to support the P450-dependent 6 beta-hydroxylation of testosterone by the fusion protein were seen. Addition of a4-fold excess of purified NADPH-P450 reductase, in the presence of phospholipid, detergent, and b(5), stimulates the rate of testosterone 6beta-hydroxylation approximately 10-fold, providing turnover rates ashigh as 80 min(-1) for P450 3A4. Approximately 30% of the rate bf hydrogen peroxide formation is not sensitive to inhibition by the P450 inhibitor ketoconazole, suggesting hydrogen peroxide (or superoxide anion) formation/directly from the reduced flavin domains of the fusion protein. it is proposed that the stimulation of NADPH oxidation observedfollowing the addition of testosterone to the fusion protein may serve as a useful means of monitoring the interaction of other substrates with this P450 and thereby permit the rapid screening of chemicals to evaluate their potential metabolism by a human P450. (C) 1995 AcademicPress, Inc.

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Documento generato il 21/01/20 alle ore 06:53:22