Document Detail


Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes.
MedLine Citation:
PMID:  18838505     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NADPH-cytochrome P450 reductase (CPR) and cytochrome-b(5) (b(5)) together with NADH-b(5) reductase (b(5)R) play important roles in cytochrome P450 3A-mediated drug metabolism via electron transfer. However, it is not clear whether variability in expression of these accessory proteins contributes to the known interindividual variability in CYP3A activity. CPR and b(5) were measured in human liver microsomes (HLMs) by spectrophotometry and immunoblotting. HLMs from elderly (>or=46 years) male donors (n=11) averaged 27% (P=0.034) and 41% (P=0.011) lower CPR levels than young (<or=45 years) male donors (n=21) for spectrophotometric and immunoblot values, respectively. Similarly, HLMs from elderly male donors averaged 43% (P=0.034) and 47% (P=0.011) lower b(5) levels than young male donors for spectrophotometric and immunoblot values, respectively. alpha-Lipoic acid and 6-propyl-2-thiouracil were evaluated for selectivity of inhibition of CPR and b(5)R activities, respectively, using recombinant enzymes and HLMs, as well as for effects on CYP3A-mediated triazolam hydroxylation in HLMs with either NADH or beta-NADPH. The results indicate that both compounds are relatively nonselective inhibitors of CPR and b(5)R activities. Finally, we used multivariate regression analysis and showed that variability in CPR or b(5) expression between HLMs does not contribute significantly to variability in CYP3A-mediated midazolam hydroxylation. Consequently, while aging is associated with decreased CPR and b(5) expression in human livers, this effect does not contribute to CYP3A variability.
Authors:
Lu Gan; Lisa L von Moltke; Lauren A Trepanier; Jerold S Harmatz; David J Greenblatt; Michael H Court
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-10-06
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  37     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-24     Completed Date:  2009-03-02     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  90-6     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.
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MeSH Terms
Descriptor/Qualifier:
Aging / metabolism
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System / metabolism*
Cytochrome-B(5) Reductase / antagonists & inhibitors,  metabolism*
Enzyme Inhibitors / pharmacology
Female
Humans
Male
Microsomes, Liver / enzymology*
NADPH-Ferrihemoprotein Reductase / antagonists & inhibitors,  metabolism*
Sex Factors
Thioctic Acid / pharmacology
Grant Support
ID/Acronym/Agency:
AG17880/AG/NIA NIH HHS; AI58784/AI/NIAID NIH HHS; R01 AG017880-05/AG/NIA NIH HHS; R01 GM061753-08/GM/NIGMS NIH HHS; R01 GM061834/GM/NIGMS NIH HHS; R01 GM061834-07/GM/NIGMS NIH HHS; R01 GM61753/GM/NIGMS NIH HHS; R21 AI058784-02/AI/NIAID NIH HHS; R21 GM074369/GM/NIGMS NIH HHS; R21 GM074369-02/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 62-46-4/Thioctic Acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/CYP3A protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; EC 1.6.2.2/Cytochrome-B(5) Reductase; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase
Comments/Corrections

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