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Query: CAS:22373-09-7 (cholestane)
 779 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4',4'-dimethylspiro (5 alpha-cholestane-3,2'-oxazolidin)-3'-yloxy (IK-1) and 7 alpha,12 alpha-dihydroxy-4',-4'-dimethylspiro (5 beta-cholan-24-oic-3,2'-oxazolidin)-3'-yloxy acid (IK-2), two stable steroidic nitroxyl radicals, were newly synthesized and tested as possible inhibitors of lipid peroxidation, induced by Fenton's reagent in both rat liver microsomes and egg phosphatidylcholine liposomes. The inhibitory activity, evaluated through the formation of thiobarbituric acid reactive substances (TBARS) and the conjugated diene, was compared with that of alpha-tocopherol and 2,2,6,6-tetramethylpiperidine-1-yloxy (TEMPO). In each model system IK-1 and IK-2 exhibited an IC50 of 8 microM and reduced the formation of TBARS and conjugated diene, showing IK-1 a potency comparable to alpha-tocopherol and higher than TEMPO. Moreover IK-1 and, to a lesser extent IK-2, reduced the lipid peroxidation induced in the microsomes by the water-soluble azo-initiator 2,2'-Azobis (2-methylpropionamidine) dihydrochloride (AMPH), indicating the IK-1 and IK-2 ability as chain-breaking antioxidants. The hydroxylamine 4',4'-dimethylspiro (5 alpha-cholestane-3,2'-oxazolidin)-3'-hydroxide (IK-3), obtained by chemical reduction of IK-1, was completely inactive as an inhibitor of lipid peroxidation in heat pre-treated microsomes and in liposomes. However in microsomes it was active since it was oxidized to the corresponding nitroxyl radical IK-1.
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PMID:Inhibition of in vitro lipid peroxidation by stable steroidic nitroxyl radicals. 931 87

3alpha-Hydroxy-5 beta-cholan-24-oic (lithocholic) acid is a relatively minor component of hepatic bile acids in humans but is highly cytotoxic. Hepatic microsomal oxidation offers a potential mechanism for effective detoxification and elimination of bile acids. The aim of the present study was to investigate the biotransformation of lithocholic acid by human hepatic microsomes and to assess the contribution of cytochrome P450 (P450) enzymes in human hepatic microsomes using human recombinant P450 enzymes and chemical inhibitors. Metabolites were identified, and metabolite formation was quantified using a liquid chromatography/mass spectrometry-based assay. Incubation of lithocholic acid with human liver microsomes resulted in the formation of five metabolites, which are listed in order of their rates of formation: 3-oxo-5 beta-cholan-24-oic (3-ketocholanoic) acid, 3 alpha,6 alpha-dihydroxy-5 beta-cholan-24-oic (hyodeoxycholic) acid, 3 alpha,7 beta-dihydroxy-5 beta-cholan-24-oic (ursodeoxycholic) acid, 3 alpha,6 beta-dihydroxy-5 beta-cholan-24-oic (murideoxycholic) acid, and 3 alpha-hydroxy-6-oxo-5 beta-cholan-24-oic (6-ketolithocholic) acid. 3-Ketocholanoic acid was the major metabolite, exhibiting apparent K(m) and V(max) values of 22 muM and 336 pmol/min/mg protein, respectively. Incubation of lithocholic acid with a of human recombinant P450 enzymes revealed that all five metabolites were formed by recombinant CYP3A4. Chemical inhibition studies with human liver microsomes and recombinant P450 enzymes confirmed that CYP3A4 was the predominant enzyme involved in hepatic microsomal biotransformation of lithocholic acid. In summary, the results indicate that oxidation of the third carbon of the cholestane ring is the preferred position of oxidation by P450 enzymes for lithocholic acid biotransformation in humans and suggest that formation of lithocholic acid metabolites leads to enhanced hepatic detoxification and elimination.
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PMID:3-ketocholanoic acid is the major in vitro human hepatic microsomal metabolite of lithocholic acid. 1948 51


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