Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1
The metabolism of azoxymethane (AOM), methylazoxymethanol (MAM) and N-nitrosodimethylamine (NDMA) by liver microsomes from acetone-induced rats as well as by a reconstituted system containing purified cytochrome P450IIE1 was examined. The products consisted of MAM from AOM; methanol and formic acid...
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| Veröffentlicht in: | Carcinogenesis (New York) 1991-01, Vol.12 (1), p.127-131 |
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| creator | Sohn, Ock Soon Ishizaki, Hiroyuki Yang, Chung S. Fiala, Emerich S. |
| description | The metabolism of azoxymethane (AOM), methylazoxymethanol (MAM) and N-nitrosodimethylamine (NDMA) by liver microsomes from acetone-induced rats as well as by a reconstituted system containing purified cytochrome P450IIE1 was examined. The products consisted of MAM from AOM; methanol and formic acid from MAM; and methylamine, formaldehyde, methanol, methylphosphate and formic acid from NDMA. Compared to liver microsomes from untreated rats, the metabolic activity of acetone-induced microsomes was ˜4 times higher for all three carcinogens. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol P450/min) for AOM, MAM and NDMA were 2.88 ± 1.14,2.87 ± 0.59 and 9.47 ± 2.24 respectively. Incubations carried out in the presence of a monoclonal antibody to cytochrome P450IIE1 resulted in a 85–90% inhibition of all three reactions in this system. These results provide conclusive evidence that AOM, MAM and NDMA are metabolized by the same form of rat liver cytochrome P450. In addition, the stoichiometry of NDMA products formed in these reactions indicates that denitrosation, a presumed detoxication process, and α-hydroxylation, an activation reaction, are also catalyzed by the same cytochrome P450 isozyme. |
| doi_str_mv | 10.1093/carcin/12.1.127 |
| format | Article |
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The products consisted of MAM from AOM; methanol and formic acid from MAM; and methylamine, formaldehyde, methanol, methylphosphate and formic acid from NDMA. Compared to liver microsomes from untreated rats, the metabolic activity of acetone-induced microsomes was ˜4 times higher for all three carcinogens. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol P450/min) for AOM, MAM and NDMA were 2.88 ± 1.14,2.87 ± 0.59 and 9.47 ± 2.24 respectively. Incubations carried out in the presence of a monoclonal antibody to cytochrome P450IIE1 resulted in a 85–90% inhibition of all three reactions in this system. These results provide conclusive evidence that AOM, MAM and NDMA are metabolized by the same form of rat liver cytochrome P450. 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The products consisted of MAM from AOM; methanol and formic acid from MAM; and methylamine, formaldehyde, methanol, methylphosphate and formic acid from NDMA. Compared to liver microsomes from untreated rats, the metabolic activity of acetone-induced microsomes was ˜4 times higher for all three carcinogens. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol P450/min) for AOM, MAM and NDMA were 2.88 ± 1.14,2.87 ± 0.59 and 9.47 ± 2.24 respectively. Incubations carried out in the presence of a monoclonal antibody to cytochrome P450IIE1 resulted in a 85–90% inhibition of all three reactions in this system. These results provide conclusive evidence that AOM, MAM and NDMA are metabolized by the same form of rat liver cytochrome P450. In addition, the stoichiometry of NDMA products formed in these reactions indicates that denitrosation, a presumed detoxication process, and α-hydroxylation, an activation reaction, are also catalyzed by the same cytochrome P450 isozyme.</description><subject>Acetone - pharmacology</subject><subject>Animals</subject><subject>Azoxymethane - metabolism</subject><subject>Biological and medical sciences</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>Carcinogens - metabolism</subject><subject>Chemical agents</subject><subject>Cytochrome P-450 Enzyme System - physiology</subject><subject>Dimethylnitrosamine - metabolism</subject><subject>Isoenzymes - physiology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methylazoxymethanol Acetate - analogs & derivatives</subject><subject>Methylazoxymethanol Acetate - metabolism</subject><subject>Microsomes, Liver - metabolism</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Tumors</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEFv1DAQhS0EKtvCmRNSLnBqdj22YztHVBW6YtsitQjExXKcsWpI4mJnpYZfT6qsoJeZ0bxvnjSPkDdA10BrvnE2uTBsgK1hDUw9IysQkpYMNH1OVhQELznn4iU5zvknpSB5VR-RI6i1BsVWxF7iaJvYhdwX0Rf2T3yYehzv7ICnxeMwdU92sSvs0BZX5RDGFHNswwHpw4BFMxVuGqO7S7HH4ouo6HZ7Dq_IC2-7jK8P_YR8_Xh-e3ZR7q4_bc8-7EonKjWWQiJ6JRvRUA_St4x7C6ioqK2wqrXC02aeJCqwFUXNLFJXa6pp7VusHT8h7xff-xR_7zGPpg_ZYdfNr8R9NlBpzZRiM7hZQDe_kBN6c59Cb9NkgJrHUM0SqgFmYC5qvnh7sN43Pbb_-SXFWX930G12tvPJDi7kJ5gEUWmYuXLhQh7x4Z9u0y8jFVeVufj-w-hvn-ubq500Ff8LEC6R4g</recordid><startdate>199101</startdate><enddate>199101</enddate><creator>Sohn, Ock Soon</creator><creator>Ishizaki, Hiroyuki</creator><creator>Yang, Chung S.</creator><creator>Fiala, Emerich S.</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>199101</creationdate><title>Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1</title><author>Sohn, Ock Soon ; Ishizaki, Hiroyuki ; Yang, Chung S. ; Fiala, Emerich S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-46eef76b4b0f16fd23fa1e7049a4a7da4f0ba4a6e71a50e82ae0c980809fde9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Acetone - pharmacology</topic><topic>Animals</topic><topic>Azoxymethane - metabolism</topic><topic>Biological and medical sciences</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Carcinogens - metabolism</topic><topic>Chemical agents</topic><topic>Cytochrome P-450 Enzyme System - physiology</topic><topic>Dimethylnitrosamine - metabolism</topic><topic>Isoenzymes - physiology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Methylazoxymethanol Acetate - analogs & derivatives</topic><topic>Methylazoxymethanol Acetate - metabolism</topic><topic>Microsomes, Liver - metabolism</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sohn, Ock Soon</creatorcontrib><creatorcontrib>Ishizaki, Hiroyuki</creatorcontrib><creatorcontrib>Yang, Chung S.</creatorcontrib><creatorcontrib>Fiala, Emerich S.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sohn, Ock Soon</au><au>Ishizaki, Hiroyuki</au><au>Yang, Chung S.</au><au>Fiala, Emerich S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>1991-01</date><risdate>1991</risdate><volume>12</volume><issue>1</issue><spage>127</spage><epage>131</epage><pages>127-131</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>The metabolism of azoxymethane (AOM), methylazoxymethanol (MAM) and N-nitrosodimethylamine (NDMA) by liver microsomes from acetone-induced rats as well as by a reconstituted system containing purified cytochrome P450IIE1 was examined. The products consisted of MAM from AOM; methanol and formic acid from MAM; and methylamine, formaldehyde, methanol, methylphosphate and formic acid from NDMA. Compared to liver microsomes from untreated rats, the metabolic activity of acetone-induced microsomes was ˜4 times higher for all three carcinogens. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol P450/min) for AOM, MAM and NDMA were 2.88 ± 1.14,2.87 ± 0.59 and 9.47 ± 2.24 respectively. Incubations carried out in the presence of a monoclonal antibody to cytochrome P450IIE1 resulted in a 85–90% inhibition of all three reactions in this system. These results provide conclusive evidence that AOM, MAM and NDMA are metabolized by the same form of rat liver cytochrome P450. 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| ispartof | Carcinogenesis (New York), 1991-01, Vol.12 (1), p.127-131 |
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| language | eng |
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| source | Oxford University Press Journals Digital Archive legacy; MEDLINE |
| subjects | Acetone - pharmacology Animals Azoxymethane - metabolism Biological and medical sciences Carcinogenesis, carcinogens and anticarcinogens Carcinogens - metabolism Chemical agents Cytochrome P-450 Enzyme System - physiology Dimethylnitrosamine - metabolism Isoenzymes - physiology Male Medical sciences Methylazoxymethanol Acetate - analogs & derivatives Methylazoxymethanol Acetate - metabolism Microsomes, Liver - metabolism Rats Rats, Inbred Strains Tumors |
| title | Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1 |
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