Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate

Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol., 43, 115-119). Ra...

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Veröffentlicht in:Archives of biochemistry and biophysics 1993-05, Vol.303 (1), p.172-176
Hauptverfasser: Bradford, B.U., Seed, C.B., Handler, J.A., Forman, D.T., Thurman, R.G.
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container_issue 1
container_start_page 172
container_title Archives of biochemistry and biophysics
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creator Bradford, B.U.
Seed, C.B.
Handler, J.A.
Forman, D.T.
Thurman, R.G.
description Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol., 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH −) deer mice because the H 2O 2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH − deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH + deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 ± 4 nmol/min/mg protein in 10,000 g pellets from ADH − deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH − deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H 2O 2 supply. In the ADH + deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH − deer mouse. The contribution of catalase was about 50% in the ADH + mutan
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U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol., 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH −) deer mice because the H 2O 2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH − deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH + deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 ± 4 nmol/min/mg protein in 10,000 g pellets from ADH − deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH − deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H 2O 2 supply. In the ADH + deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH − deer mouse. 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Miscellaneous ; Methanol - metabolism ; Olive Oil ; Other biological molecules ; Oxidation-Reduction ; Peromyscus ; Plant Oils - pharmacology</subject><ispartof>Archives of biochemistry and biophysics, 1993-05, Vol.303 (1), p.172-176</ispartof><rights>1993 Academic Press</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c283t-22f0480d19627b7f96e56f754946ba1a3a57d2b461fc2aaaaf76894d01a399253</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0003986183712695$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=4755408$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8489262$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bradford, B.U.</creatorcontrib><creatorcontrib>Seed, C.B.</creatorcontrib><creatorcontrib>Handler, J.A.</creatorcontrib><creatorcontrib>Forman, D.T.</creatorcontrib><creatorcontrib>Thurman, R.G.</creatorcontrib><title>Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate</title><title>Archives of biochemistry and biophysics</title><addtitle>Arch Biochem Biophys</addtitle><description>Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol., 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH −) deer mice because the H 2O 2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH − deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH + deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 ± 4 nmol/min/mg protein in 10,000 g pellets from ADH − deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH − deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H 2O 2 supply. In the ADH + deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH − deer mouse. The contribution of catalase was about 50% in the ADH + mutant at low doses of ethanol and approached 100% as the alcohol concentration was elevated.</description><subject>Alcohol Dehydrogenase - metabolism</subject><subject>Amitrole - pharmacology</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Catalase - antagonists &amp; inhibitors</subject><subject>Catalase - metabolism</subject><subject>Ethanol - metabolism</subject><subject>Fructose - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Intermediary metabolites. Miscellaneous</subject><subject>Methanol - metabolism</subject><subject>Olive Oil</subject><subject>Other biological molecules</subject><subject>Oxidation-Reduction</subject><subject>Peromyscus</subject><subject>Plant Oils - pharmacology</subject><issn>0003-9861</issn><issn>1096-0384</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9v1DAQxS1EVZbClRuSD4hbtrbjODE3tF2gUlet-oerNUkmrKtsvLWdhX4NPjGONuoNX3x4vzczeo-QD5wtOWPqHOraLrnW-ZILpV-RBWdaZSyv5GuyYIzlma4Uf0PehvDIGOdSiVNyWslKCyUW5O_6YFscGqT3W4h0BRF6CEgvAwW6gUfn6Q3E7W94pq6j67iFwfX0-o9tIVo3UDvQn_bgvtALFzC7xbB3Q7LfxbG1GCb5AtHTjU0bHoIdftENzkNgWnGHPTbRHpJlrEP0EPEdOemgD_h-_s_Iw7f1_epHdnX9_XL19SprRJXHTIiOyYq1XCtR1mWnFRaqKwuppaqBQw5F2YpaKt41AtLrSlVp2bIkaS2K_Ix8Ps7de_c0YohmZ0ODfQ8DujGYsihFXgqWwOURbLwLwWNn9t7uwD8bzsxUgplKMFMJZiohGT7Ok8d6h-0LPqee9E-zDqGBvvMwNDa8YLIsCsmqhFVHDFMKB4vehMZOXbXWp9BM6-z_LvgHzXOidQ</recordid><startdate>19930515</startdate><enddate>19930515</enddate><creator>Bradford, B.U.</creator><creator>Seed, C.B.</creator><creator>Handler, J.A.</creator><creator>Forman, D.T.</creator><creator>Thurman, R.G.</creator><general>Elsevier Inc</general><general>Elsevier</general><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>7X8</scope></search><sort><creationdate>19930515</creationdate><title>Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate</title><author>Bradford, B.U. ; Seed, C.B. ; Handler, J.A. ; Forman, D.T. ; Thurman, R.G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c283t-22f0480d19627b7f96e56f754946ba1a3a57d2b461fc2aaaaf76894d01a399253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Alcohol Dehydrogenase - metabolism</topic><topic>Amitrole - pharmacology</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Catalase - antagonists &amp; inhibitors</topic><topic>Catalase - metabolism</topic><topic>Ethanol - metabolism</topic><topic>Fructose - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Intermediary metabolites. Miscellaneous</topic><topic>Methanol - metabolism</topic><topic>Olive Oil</topic><topic>Other biological molecules</topic><topic>Oxidation-Reduction</topic><topic>Peromyscus</topic><topic>Plant Oils - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bradford, B.U.</creatorcontrib><creatorcontrib>Seed, C.B.</creatorcontrib><creatorcontrib>Handler, J.A.</creatorcontrib><creatorcontrib>Forman, D.T.</creatorcontrib><creatorcontrib>Thurman, R.G.</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>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Archives of biochemistry and biophysics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bradford, B.U.</au><au>Seed, C.B.</au><au>Handler, J.A.</au><au>Forman, D.T.</au><au>Thurman, R.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate</atitle><jtitle>Archives of biochemistry and biophysics</jtitle><addtitle>Arch Biochem Biophys</addtitle><date>1993-05-15</date><risdate>1993</risdate><volume>303</volume><issue>1</issue><spage>172</spage><epage>176</epage><pages>172-176</pages><issn>0003-9861</issn><eissn>1096-0384</eissn><coden>ABBIA4</coden><abstract>Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol., 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH −) deer mice because the H 2O 2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH − deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH + deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 ± 4 nmol/min/mg protein in 10,000 g pellets from ADH − deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH − deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H 2O 2 supply. In the ADH + deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH − deer mouse. The contribution of catalase was about 50% in the ADH + mutant at low doses of ethanol and approached 100% as the alcohol concentration was elevated.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>8489262</pmid><doi>10.1006/abbi.1993.1269</doi><tpages>5</tpages></addata></record>
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ispartof Archives of biochemistry and biophysics, 1993-05, Vol.303 (1), p.172-176
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subjects Alcohol Dehydrogenase - metabolism
Amitrole - pharmacology
Analytical, structural and metabolic biochemistry
Animals
Biological and medical sciences
Catalase - antagonists & inhibitors
Catalase - metabolism
Ethanol - metabolism
Fructose - pharmacology
Fundamental and applied biological sciences. Psychology
Intermediary metabolites. Miscellaneous
Methanol - metabolism
Olive Oil
Other biological molecules
Oxidation-Reduction
Peromyscus
Plant Oils - pharmacology
title Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate
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