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Titolo:
Sex-dependent toxicity of a novel acyl-CoA : cholesterol acyltransferase inhibitor, YIC-C8-434, in relation to sex-specific forms of cytochrome P450 in rats
Autore:
Kaneko, K; Uchida, K; Kobayashi, T; Miura, K; Tanokura, K; Hoshino, K; Kato, I; Onoue, M; Yokokura, T;
Indirizzi:
Yakult Cent Inst Microbiol Res, Kunitachi, Tokyo 1868650, Japan Yakult Cent Inst Microbiol Res Kunitachi Tokyo Japan 1868650 68650, Japan
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 2, volume: 64, anno: 2001,
pagine: 259 - 268
SICI:
1096-6080(200112)64:2<259:STOANA>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
COENZYME-A; ANTIATHEROSCLEROTIC AGENTS; ESTERIFICATION ENZYMES; MOLECULAR-CLONING; ADRENAL TOXICITY; ACAT INHIBITORS; LIPID REGULATOR; GROWTH-HORMONE; BEAGLE DOGS; EXPRESSION;
Keywords:
rats; ACAT inhibitor; toxicity; sex differences; hepatic CYP enzymes; CYP3A2;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Kaneko, K Yakult Cent Inst Microbiol Res, 1796 Yaho, Kunitachi, Tokyo 1868650, Japan Yakult Cent Inst Microbiol Res 1796 Yaho Kunitachi Tokyo Japan 1868650
Citazione:
K. Kaneko et al., "Sex-dependent toxicity of a novel acyl-CoA : cholesterol acyltransferase inhibitor, YIC-C8-434, in relation to sex-specific forms of cytochrome P450 in rats", TOXICOL SCI, 64(2), 2001, pp. 259-268

Abstract

YIC-C8-434 is a novel inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT). To clarify the toxicity of YIC-C8-434, the compound was given orally to Sprague-Dawley rats for 28 days at 0, 4, 20, 100, or 500 mg/kg/day. The toxicity of the drug differed significantly between male and female rats. In female rats treated at 500 mg/kg, many symptoms including moribundcondition, suppression of weight gain and food consumption, abnormal bloodchemistry, and decreases in organ weights (thymus, ovaries, and uterus) were observed. In male rats by contrast, no significant toxicity was observedat any dose. After a single administration of YIC-C8-434 at 500 mg/kg, female rats had a higher blood concentration of the compound than male rats. Little elimination of YIC-C8-434 was observed in female rats on analysis of drug-elimination kinetics. Furthermore, the metabolism of YIC-C8-434 was analyzed using rat hepatic microsomal preparations from both sexes. Consistent with the observations in vivo, hepatic microsomes from male rats better metabolized YIC-C8-434 than those from females. In addition, the metabolism of YIC-C8-434 by hepatic microsomes from male rats was blocked by SKF525A, a P450 inhibitor. Inhibition experiments using anti-rat CYP1A1, CYP1A2, CYP2B1, CYP2C11, CYP2E1, CYP3A2, and CYP4A1 antisera indicated that CYP3A2 played the predominant role in the metabolism of YIC-C8-434 in rats. Since there is less CYP3A2 in the liver of female than male rats, the involvement ofCYP3A2 in YIC-C8-434 metabolism has implications for the sex-related metabolic activity and toxicity of YIC-C8-434.

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Documento generato il 20/09/20 alle ore 00:32:21