Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4
- Department of Bioscience, University of Strathclyde, 204 George Street, Glasgow, G1 1XW Scotland (United Kingdom)
- Department of Pharmaceutical Sciences, University of Strathclyde, 204 George Street, Glasgow, G1 1XW Scotland (United Kingdom)
- Division of Cardiology, School of Medicine, University of Louisville, 580 S. Preston St., Louisville, KY 40202 (United States)
- School of Science and Technology, Bell College, Almada Street, Hamilton ML3 0JB (United Kingdom)
- Department of Bioscience, University of Strathclyde, 204 George Street, Glasgow, G1 1XW Scotland (United Kingdom) and Department of Pharmaceutical Sciences, University of Strathclyde, 204 George Street, Glasgow, G1 1XW Scotland (United Kingdom)
The reductive metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, was studied in mouse liver. Using an HPLC-based stopped assay, the primary reduced metabolite was identified as 6-hydroxy-trans, trans-2,4-hexadienal (OH/CHO) and the secondary metabolite as 1,6-dihydroxy-trans, trans-2,4-hexadiene (OH/OH). The main enzymes responsible for the highest levels of reductase activity towards trans, trans-muconaldehyde were purified from mouse liver soluble fraction first by Q-sepharose chromatography followed by either blue or red dye affinity chromatography. In mouse liver, trans, trans-muconaldehyde is predominantly reduced by an NADH-dependent enzyme, which was identified as alcohol dehydrogenase (Adh1). Kinetic constants obtained for trans, trans-muconaldehyde with the native Adh1 enzyme showed a V {sub max} of 2141 {+-} 500 nmol/min/mg and a K {sub m} of 11 {+-} 4 {mu}M. This enzyme was inhibited by pyrazole with a K {sub I} of 3.1 {+-} 0.57 {mu}M. Other fractions were found to contain muconaldehyde reductase activity independent of Adh1, and one enzyme was identified as the NADPH-dependent aldehyde reductase AKR1A4. This showed a V {sub max} of 115 nmol/min/mg and a K {sub m} of 15 {+-} 2 {mu}M and was not inhibited by pyrazole.
- OSTI ID:
- 20783415
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 210, Issue 1-2; Other Information: DOI: 10.1016/j.taap.2005.09.017; PII: S0041-008X(05)00578-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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