Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/ NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes
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...
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| Veröffentlicht in: | Drug metabolism and disposition 2009-01, Vol.37 (1), p.90-96 |
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| creator | LU GAN VON MOLTKE, Lisa L TREPANIER, Lauren A HARMATZ, Jerold S GREENBLATT, David J COURT, Michael H |
| description | 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 ( |
| doi_str_mv | 10.1124/dmd.108.023424 |
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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.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.108.023424</identifier><identifier>PMID: 18838505</identifier><identifier>CODEN: DMDSAI</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Aging - metabolism ; Biological and medical sciences ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome-B Reductase - antagonists & inhibitors ; Cytochrome-B Reductase - metabolism ; Enzyme Inhibitors - pharmacology ; Female ; Humans ; Male ; Medical sciences ; Microsomes, Liver - enzymology ; NADPH-Ferrihemoprotein Reductase - antagonists & inhibitors ; NADPH-Ferrihemoprotein Reductase - metabolism ; Pharmacology. Drug treatments ; Sex Factors ; Thioctic Acid - pharmacology</subject><ispartof>Drug metabolism and disposition, 2009-01, Vol.37 (1), p.90-96</ispartof><rights>2009 INIST-CNRS</rights><rights>Copyright © 2009, The American Society for Pharmacology and Experimental Therapeutics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20998695$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18838505$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LU GAN</creatorcontrib><creatorcontrib>VON MOLTKE, Lisa L</creatorcontrib><creatorcontrib>TREPANIER, Lauren A</creatorcontrib><creatorcontrib>HARMATZ, Jerold S</creatorcontrib><creatorcontrib>GREENBLATT, David J</creatorcontrib><creatorcontrib>COURT, Michael H</creatorcontrib><title>Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/ NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>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.</description><subject>Aging - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome-B Reductase - antagonists & inhibitors</subject><subject>Cytochrome-B Reductase - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - enzymology</subject><subject>NADPH-Ferrihemoprotein Reductase - antagonists & inhibitors</subject><subject>NADPH-Ferrihemoprotein Reductase - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Sex Factors</subject><subject>Thioctic Acid - pharmacology</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1PGzEQhq0KVALtlSPyBW4b_J31pVKUAkEKNEJQtafVrO0trnbXqb0bKb-Av81GBAqnGfl9_IxmEDqmZEwpE-e2sWNK8jFhXDDxCY2oZDQjRP_aQ6OhkExLqQ7QYUp_CaFCcP0ZHdA857kkcoSe7kLtcKjw7fT7cp7NNl0wjzE0Di-FJPjO2d50kByG1uL_aVbK8-2X-dC8g3yLf0L0UPrad5utdvZ7yad4ajq_3r4MwLxvoMULv3YR33gTQxp86Qvar6BO7uuuHqGHy4v72Txb_Li6nk0X2Yry7TLc5UIJWmonqgmvrDNgQYMEZoiQmk6E0bxUljsNueJSsapUzsqKKTsZoiP07cW76svGWePaLkJdrKJvIG6KAL74mLT-sfgT1gVTlDBBBsHZThDDv96lrmh8Mq6uoXWhT4VSE8lkzgbw5P2ktxGvtx-A0x0AyUBdRWiNT28cI1rnSkv-DHOrk1I</recordid><startdate>200901</startdate><enddate>200901</enddate><creator>LU GAN</creator><creator>VON MOLTKE, Lisa L</creator><creator>TREPANIER, Lauren A</creator><creator>HARMATZ, Jerold S</creator><creator>GREENBLATT, David J</creator><creator>COURT, Michael H</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200901</creationdate><title>Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/ NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes</title><author>LU GAN ; VON MOLTKE, Lisa L ; TREPANIER, Lauren A ; HARMATZ, Jerold S ; GREENBLATT, David J ; COURT, Michael H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p1390-93e84641b9e4f73fdecada9a5a2c0459174c93b6d3e9a863562fb6ed5f26d7c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aging - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Cytochrome-B Reductase - antagonists & inhibitors</topic><topic>Cytochrome-B Reductase - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - enzymology</topic><topic>NADPH-Ferrihemoprotein Reductase - antagonists & inhibitors</topic><topic>NADPH-Ferrihemoprotein Reductase - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Sex Factors</topic><topic>Thioctic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LU GAN</creatorcontrib><creatorcontrib>VON MOLTKE, Lisa L</creatorcontrib><creatorcontrib>TREPANIER, Lauren A</creatorcontrib><creatorcontrib>HARMATZ, Jerold S</creatorcontrib><creatorcontrib>GREENBLATT, David J</creatorcontrib><creatorcontrib>COURT, Michael H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LU GAN</au><au>VON MOLTKE, Lisa L</au><au>TREPANIER, Lauren A</au><au>HARMATZ, Jerold S</au><au>GREENBLATT, David J</au><au>COURT, Michael H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/ NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2009-01</date><risdate>2009</risdate><volume>37</volume><issue>1</issue><spage>90</spage><epage>96</epage><pages>90-96</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><coden>DMDSAI</coden><abstract>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.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>18838505</pmid><doi>10.1124/dmd.108.023424</doi><tpages>7</tpages></addata></record> |
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| ispartof | Drug metabolism and disposition, 2009-01, Vol.37 (1), p.90-96 |
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| subjects | Aging - metabolism Biological and medical sciences Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism Cytochrome-B Reductase - antagonists & inhibitors Cytochrome-B Reductase - metabolism Enzyme Inhibitors - pharmacology Female Humans Male Medical sciences Microsomes, Liver - enzymology NADPH-Ferrihemoprotein Reductase - antagonists & inhibitors NADPH-Ferrihemoprotein Reductase - metabolism Pharmacology. Drug treatments Sex Factors Thioctic Acid - pharmacology |
| title | Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/ NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes |
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