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Functional characterization of eight human CYP1A2 variants: the role of cytochrome b5.
MedLine Citation:
PMID:  23295917     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
BACKGROUND: Interindividual variability in cytochrome P450 (CYP)-mediated xenobiotic metabolism is extensive. CYP metabolism requires two electrons, which can be donated by NADPH cytochrome P450 oxidoreductase (CYPOR) and/or cytochrome b5 (b5). Although substantial number of studies have reported on the function and effect of b5 in CYP-mediated catalysis, its mode of action is still not fully understood.
OBJECTIVE: The aim of this work was to examine the effect of b5 on the activities of eight natural-occurring variants of human CYP1A2, namely, T83M, S212C, S298R, G299S, I314V, I386F, C406Y, and R456H.
MATERIALS AND METHODS: An approach, as used in our former study was applied, coexpressing these polymorphic CYP1A2 variants separately with CYPOR and b5 in the bacterial cell model BTC-CYP. For each variant, 16 different activity parameters were measured, using eight different substrates. This heterogeneous data set was merged with the one of our former study (i.e. without b5) and a multivariate analysis was carried out.
RESULTS: This analysis indicated that b5 seems to have the ability to affect CYP1A2 variants to behave more like the wild-type variant. This was especially the case for variant I386F, for which the presence of b5 was crucial to show activity. Variants T83M and C406Y showed considerably different activity-profiles when in the presence of b5. Furthermore, our data seem to implicate CYP1A2 residue G299 in its interaction with CYPOR and/or b5.
CONCLUSION: Results indicate the ability of b5 to affect CYP1A2 variants to behave more like the wild-type variant, attenuating detrimental effects of structural mutations of these variants, seemingly through extensive allosteric effects.
Authors:
Bernardo B Palma; Marta Silva E Sousa; Phillipe Urban; José Rueff; Michel Kranendonk
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  23     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-08     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  41-52     Citation Subset:  IM    
Affiliation:
aDepartment of Genetics, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal bUniversity of Toulouse, INSA, UPS, INP, LISBP cINRA, UMR 792 Laboratory of Biological Systems and Process Engineering dCNRS, UMR5504, Toulouse, France.
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