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Titolo:
Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A aremarkedly up-regulated in Cyp27(-/-) mice but not in cerebrotendinous xanthomatosis
Autore:
Honda, A; Salen, G; Matsuzaki, Y; Batta, AK; Xu, GR; Leitersdorf, E; Ting, GS; Erickson, SK; Tanaka, N; Shefer, S;
Indirizzi:
Univ Tsukuba, Dept Gastroenterol, Tsukuba, Ibaraki 3058575, Japan Univ Tsukuba Tsukuba Ibaraki Japan 3058575 sukuba, Ibaraki 3058575, Japan Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, GastrointestinalDiv, Newark, NJ 07103 USA Univ Med & Dent New Jersey Newark NJ USA 07103 lDiv, Newark, NJ 07103 USA Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Liver, Newark, NJ 07103 USA Univ Med & Dent New Jersey Newark NJ USA 07103 iver, Newark, NJ 07103 USA Hadassah Univ Hosp, Dept Med, Ctr Res Prevent & Treatment Atherosclerosis,IL-91120 Jerusalem, Israel Hadassah Univ Hosp Jerusalem Israel IL-91120 ,IL-91120 Jerusalem, Israel Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA Univ CalifSan Francisco San Francisco CA USA 94121 ancisco, CA 94121 USA Vet Affairs Med Ctr, San Francisco, CA 94121 USA Vet Affairs Med Ctr San Francisco CA USA 94121 an Francisco, CA 94121 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 37, volume: 276, anno: 2001,
pagine: 34579 - 34585
SICI:
0021-9258(20010914)276:37<34579:SCHIBA>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
STEROL 27-HYDROXYLASE GENE; PERFORMANCE LIQUID-CHROMATOGRAPHY; RAT-LIVER MITOCHONDRIA; CHENODEOXYCHOLIC ACID; CHOLESTEROL 7-ALPHA-HYDROXYLASE; ALCOHOL GLUCURONIDES; MASS-SPECTROMETRY; 25-HYDROXYLATION; MICROSOMES; MUTATIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Salen, G Vet Affairs Med Ctr, GI Lab 15A, 385 Tremont Ave, E Orange, NJ 07018 USA Vet Affairs Med Ctr 385 Tremont Ave E Orange NJ USA 07018 018 USA
Citazione:
A. Honda et al., "Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A aremarkedly up-regulated in Cyp27(-/-) mice but not in cerebrotendinous xanthomatosis", J BIOL CHEM, 276(37), 2001, pp. 34579-34585

Abstract

The accumulation of various 25-hydroxylated C-27-bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27)gene. These bile alcohols may be intermediates in the alternative cholic acid side chain cleavage pathway. The present study was undertaken to identify enzymes and reactions responsible for the formation of these bile alcohols and to explain why Cyp27(-/-) mice do not show CTX-related abnormalities. Microsomal activities of 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha -triol 25- and 26-hydroxylases, 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha,25-tetrol 23R-, 24S-, and 27-hydroxylases and testosterone 6 beta -hydroxylase, a marker enzyme for CYP3A, in Cyp27(-/-) mice livers were markedly up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold, respectively). In contrast, these enzyme activities were not increased in CTX. The activitiesof 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha -triol 25- and 26-hydroxylases and 5p-cholestane-3a,7a,12a,25-tetrol 23R-, 24R-, 24S-, and 27-hydroxylases were strongly correlated with the activities of testosterone 6 beta -hydroxylase in control human liver microsomes from eight unrelated donors. Troleandomycin, a specific inhibitor of CYP3A, markedly suppressed these microsomal side chain hydroxylations in both mouse and human livers in a dose-dependent manner. In addition, experiments using recombinant overexpressed human CYP3A4 confirmed that these microsomal side chain hydroxylations were catalyzed by a single enzyme, CYP3A4. The results demonstrate that microsomal 25- and 26-hydroxylations of 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha -triol and microsomal 23R-, 24R-, 24S-, and 27-hydroxylations of 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha ,25-tetrol are mainly catalyzed by CYP3A in both mice and humans. Unlike Cyp27(-/-) mice, CYP3A activity wasnot up-regulated despite marked accumulation of 5 beta -cholestane-3 alpha,7 alpha ,12 alpha -triol in CTX.

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Documento generato il 11/07/20 alle ore 16:12:34