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Titolo:
BACULOVIRUS-MEDIATED EXPRESSION AND CHARACTERIZATION OF RAT CYP2A3 AND HUMAN CYP2A6 - ROLE IN METABOLIC-ACTIVATION OF NASAL TOXICANTS
Autore:
LIU C; ZHUO XL; GONZALEZ FJ; DING XX;
Indirizzi:
NEW YORK STATE DEPT HLTH,WADSWORTH CTR LABS & RES,LAB HUMAN TOXICOL &MOL EPIDEMIOL ALBANY NY 12201 NEW YORK STATE DEPT HLTH,WADSWORTH CTR LABS & RES,LAB HUMAN TOXICOL &MOL EPIDEMIOL ALBANY NY 12201 SUNY ALBANY,SCH PUBL HLTH,DEPT ENVIRONM HLTH & TOXICOL ALBANY NY 12201 NCI,MOL CARCINOGENESIS LAB,NATL INST HLTH BETHESDA MD 20892
Titolo Testata:
Molecular pharmacology
fascicolo: 4, volume: 50, anno: 1996,
pagine: 781 - 788
SICI:
0026-895X(1996)50:4<781:BEACOR>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
STEROID 15-ALPHA-HYDROXYLASE; CYTOCHROME-P-450 ISOZYME; COUMARIN 7-HYDROXYLATION; II P-45015-ALPHA; RABBIT; MICROSOMES; SEQUENCE; CDNA; GENE; IDENTIFICATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
C. Liu et al., "BACULOVIRUS-MEDIATED EXPRESSION AND CHARACTERIZATION OF RAT CYP2A3 AND HUMAN CYP2A6 - ROLE IN METABOLIC-ACTIVATION OF NASAL TOXICANTS", Molecular pharmacology, 50(4), 1996, pp. 781-788

Abstract

Cytochrome P450 2A3 (CYP2A3) was previously identified in rat lung bycDNA cloning and recently found to be expressed at a high level in the olfactory mucosa. In the current study, CYP2A3 was expressed in insect cells lacking endogenous cytochrome P450 (P450) activity, and the substrate specificity of the recombinant cytochrome was characterized and compared with that of CYP2A6, a human ortholog of rat CYP2A3, whichhas been detected in human olfactory mucosa as well as in liver. The CYP2A3 and CYP2A6 cDNAs were cloned into baculovirus, and recombinant viruses were used to produce active enzymes in Spodoptera frugiperta (SF9) cells. The metabolic activities of S. frugiperta cell microsomal fractions containing CYP2A3 or CYP2A6 were studied in a reconstituted system with purified rabbit NADPH-P450 reductase. CYP2A3 was found to be active toward testosterone, producing 15 alpha-hydroxytestosterone and several other metabolites, but it had only low activity toward coumarin. On the other hand, CYP2A6 was active toward coumarin but not toward testosterone. However, both enzymes were active in the metabolic activation of hexamethylphosphoramide, a nasal procarcinogen, and 2,6-dichlorobenzonitrile (DCBN), a herbicide known to cause tissue-specific toxicity in the olfactory mucosa of rodents at very low doses. In addition, both enzymes were active toward 4-nitrophenol, a preferred substrate for CYP2E1. Consistent with CYP2A3 being a major catalyst in microsomal metabolism of DCBN, the activities of both CYP2A3 and rat olfactory microsomes in DCBN metabolism were inhibited strongly by metyrapone and methoxsalen (ID50 <1 mu M, with DCBN at 30 mu M), but only marginally by 4-methylpyrazole, an inhibitor of CYP2E1. In contrast, theactivity of CYP2A6 was only weakly inhibited by metyrapone or methoxsalen (ID50 >50 mu M). Thus, rat CYP2A3 and human CYP2A6 have differences in substrate specificity as well as tissue distribution. These findings should be taken into account when assessing the risk of exposure to potential nasal toxicants in humans.

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Documento generato il 08/07/20 alle ore 07:39:31