| pubmed-article:17344335 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C0205245 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C1413154 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C0032529 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C1264638 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C0243102 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C2611153 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C1510827 | lld:lifeskim |
| pubmed-article:17344335 | lifeskim:mentions | umls-concept:C2604870 | lld:lifeskim |
| pubmed-article:17344335 | pubmed:issue | 6 | lld:pubmed |
| pubmed-article:17344335 | pubmed:dateCreated | 2007-5-21 | lld:pubmed |
| pubmed-article:17344335 | pubmed:abstractText | Human carbonyl reductase 1 (CBR1) metabolizes endogenous and xenobiotic substrates such as the fever mediator, prostaglandin E2 (PGE2), and the anticancer anthracycline drug, daunorubicin. We screened 33 CBR1 full-length cDNA samples from white and black liver donors and performed database analyses to identify genetic determinants of CBR1 activity. We pinpointed a single nucleotide polymorphism on CBR1 (CBR1 V88I) that encodes for a valine-to-isoleucine substitution for further characterization. We detected the CBR1 V88I polymorphism in DNA samples from individuals with African ancestry (p = 0.986, q = 0.014). Kinetic studies revealed that the CBR1 V88 and CBR1 I88 isoforms have different maximal velocities for daunorubicin (V(max) CBR1 V88, 181 +/- 13 versus V(max) CBR1 I88, 121 +/- 12 nmol/min . mg, p < 0.05) and PGE2 (V(max) CBR1 V88, 53 +/- 7 versus V(max) CBR1 I88, 35 +/- 4 nmol/min . mg, p < 0.01). Concomitantly, CBR1 V88 produced higher levels of the cardiotoxic metabolite daunorubicinol compared with CBR1 I88 (1.7-fold, p < 0.0001). Inhibition studies demonstrated that CBR1 V88 and CBR1 I88 are distinctively inhibited by the flavonoid, rutin (IC50 CBR1 V88, 54.0 +/- 0.4 microM versus IC50 CBR1 I88, 15.0 +/- 0.1 microM, p < 0.001). Furthermore, isothermal titration calorimetry analyses together with molecular modeling studies showed that CBR1 V88I results in CBR1 isoforms with different binding affinities for the cofactor NADPH (K(d) CBR1 V88, 6.3 +/- 0.6 microM versus K(d) CBR1 I88, 3.8 +/- 0.5 microM). These studies characterize the first functional genetic determinant of CBR1 activity toward relevant physiological and pharmacological substrates. | lld:pubmed |
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| pubmed-article:17344335 | pubmed:language | eng | lld:pubmed |
| pubmed-article:17344335 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17344335 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:17344335 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:17344335 | pubmed:month | Jun | lld:pubmed |
| pubmed-article:17344335 | pubmed:issn | 0090-9556 | lld:pubmed |
| pubmed-article:17344335 | pubmed:author | pubmed-author:GhoshDebashis... | lld:pubmed |
| pubmed-article:17344335 | pubmed:author | pubmed-author:PendyalaLaksh... | lld:pubmed |
| pubmed-article:17344335 | pubmed:author | pubmed-author:BlancoJavier... | lld:pubmed |
| pubmed-article:17344335 | pubmed:author | pubmed-author:LakhmanSukhwi... | lld:pubmed |
| pubmed-article:17344335 | pubmed:author | pubmed-author:Gonzalez-Cova... | lld:pubmed |
| pubmed-article:17344335 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:17344335 | pubmed:volume | 35 | lld:pubmed |
| pubmed-article:17344335 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:17344335 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:17344335 | pubmed:pagination | 973-80 | lld:pubmed |
| pubmed-article:17344335 | pubmed:dateRevised | 2011-9-21 | lld:pubmed |
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| pubmed-article:17344335 | pubmed:meshHeading | pubmed-meshheading:17344335... | lld:pubmed |
| pubmed-article:17344335 | pubmed:year | 2007 | lld:pubmed |
| pubmed-article:17344335 | pubmed:articleTitle | A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity. | lld:pubmed |
| pubmed-article:17344335 | pubmed:affiliation | Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14260-1200, USA. | lld:pubmed |
| pubmed-article:17344335 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:17344335 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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