Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6
1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory pote...
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| Veröffentlicht in: | British journal of pharmacology 1995-11, Vol.116 (6), p.2625-2630 |
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| creator | KINONEN, T PASANEN, M GYNTHER, J POSO, A JÄRVINEN, T ALHAVA, E JUVONEN, R. O |
| description | 1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s. |
| doi_str_mv | 10.1111/j.1476-5381.1995.tb17217.x |
| format | Article |
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O</creator><creatorcontrib>KINONEN, T ; PASANEN, M ; GYNTHER, J ; POSO, A ; JÄRVINEN, T ; ALHAVA, E ; JUVONEN, R. O</creatorcontrib><description>1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/j.1476-5381.1995.tb17217.x</identifier><identifier>PMID: 8590980</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing</publisher><subject>Animals ; Aryl Hydrocarbon Hydroxylases ; Binding Sites ; Binding, Competitive ; Biological and medical sciences ; Coumarins - metabolism ; Cytochrome P-450 CYP2A6 ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - metabolism ; Enzyme Inhibitors - pharmacology ; Female ; Humans ; Hydroxylation - drug effects ; Immunomodulators ; Kinetics ; Male ; Medical sciences ; Mice ; Mice, Inbred DBA ; Microsomes, Liver - enzymology ; Mixed Function Oxygenases - antagonists & inhibitors ; Mixed Function Oxygenases - metabolism ; Models, Chemical ; Parasympathomimetics - metabolism ; Parasympathomimetics - pharmacology ; Pharmacology. Drug treatments ; Pilocarpine - metabolism ; Pilocarpine - pharmacology</subject><ispartof>British journal of pharmacology, 1995-11, Vol.116 (6), p.2625-2630</ispartof><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1909112/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1909112/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2907645$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8590980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KINONEN, T</creatorcontrib><creatorcontrib>PASANEN, M</creatorcontrib><creatorcontrib>GYNTHER, J</creatorcontrib><creatorcontrib>POSO, A</creatorcontrib><creatorcontrib>JÄRVINEN, T</creatorcontrib><creatorcontrib>ALHAVA, E</creatorcontrib><creatorcontrib>JUVONEN, R. O</creatorcontrib><title>Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s.</description><subject>Animals</subject><subject>Aryl Hydrocarbon Hydroxylases</subject><subject>Binding Sites</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Coumarins - metabolism</subject><subject>Cytochrome P-450 CYP2A6</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>Hydroxylation - drug effects</subject><subject>Immunomodulators</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred DBA</subject><subject>Microsomes, Liver - enzymology</subject><subject>Mixed Function Oxygenases - antagonists & inhibitors</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Models, Chemical</subject><subject>Parasympathomimetics - metabolism</subject><subject>Parasympathomimetics - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pilocarpine - metabolism</subject><subject>Pilocarpine - pharmacology</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhS1UVJbCT0Cyqqq3BI9jx_YFqVq1gFQJDvTQU-Q4DnGV2GnsLV1-PWaJVnDCl7Hme36aN0boHEgJ-bx_KIGJuuCVhBKU4mVqQVAQ5fMLtDmiE7QhhIgCQMpX6HWMD4RkKPgpOpVcESXJBv3chmm2ySX3ZLHzg2vzNXgcemzCbtKL81gUw75bwvN-1AfW7vHsxmD0MjtvsfYddinm18ku2hwkP1wa8BR20eLt_VdMr_hBNmRHv3bqN-hlr8do3671DN3dXH_bfipuv3z8vL26LWbKq1S0xvYdaE2IrQ0HRjvbq5YZUbPWKK5p3QMoYSQ1ljNliIaeMUokI8r2larO0Ic_vvOunWxnrE-LHpt5cTnevgnaNf8S74bme3hqIO8IgGaDy9VgCY87G1MzuWjsOGpvc8RGCFlVhKn_CoFzSTn8Fr77e6TjLOu3ZH6xch2NHvtFe-PiUUYVyel59Qu47aBw</recordid><startdate>19951101</startdate><enddate>19951101</enddate><creator>KINONEN, T</creator><creator>PASANEN, M</creator><creator>GYNTHER, J</creator><creator>POSO, A</creator><creator>JÄRVINEN, T</creator><creator>ALHAVA, E</creator><creator>JUVONEN, R. 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O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p253t-bcefd1aa00e6c5142def9b4c764bc95a26f1197c82ce549c0a1f44208409ef393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Aryl Hydrocarbon Hydroxylases</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Coumarins - metabolism</topic><topic>Cytochrome P-450 CYP2A6</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>Hydroxylation - drug effects</topic><topic>Immunomodulators</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred DBA</topic><topic>Microsomes, Liver - enzymology</topic><topic>Mixed Function Oxygenases - antagonists & inhibitors</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Models, Chemical</topic><topic>Parasympathomimetics - metabolism</topic><topic>Parasympathomimetics - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pilocarpine - metabolism</topic><topic>Pilocarpine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KINONEN, T</creatorcontrib><creatorcontrib>PASANEN, M</creatorcontrib><creatorcontrib>GYNTHER, J</creatorcontrib><creatorcontrib>POSO, A</creatorcontrib><creatorcontrib>JÄRVINEN, T</creatorcontrib><creatorcontrib>ALHAVA, E</creatorcontrib><creatorcontrib>JUVONEN, R. 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O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>1995-11-01</date><risdate>1995</risdate><volume>116</volume><issue>6</issue><spage>2625</spage><epage>2630</epage><pages>2625-2630</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s.</abstract><cop>Basingstoke</cop><pub>Nature Publishing</pub><pmid>8590980</pmid><doi>10.1111/j.1476-5381.1995.tb17217.x</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of pharmacology, 1995-11, Vol.116 (6), p.2625-2630 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals Aryl Hydrocarbon Hydroxylases Binding Sites Binding, Competitive Biological and medical sciences Coumarins - metabolism Cytochrome P-450 CYP2A6 Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Enzyme Inhibitors - pharmacology Female Humans Hydroxylation - drug effects Immunomodulators Kinetics Male Medical sciences Mice Mice, Inbred DBA Microsomes, Liver - enzymology Mixed Function Oxygenases - antagonists & inhibitors Mixed Function Oxygenases - metabolism Models, Chemical Parasympathomimetics - metabolism Parasympathomimetics - pharmacology Pharmacology. Drug treatments Pilocarpine - metabolism Pilocarpine - pharmacology |
| title | Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6 |
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