Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4 | Health & Environmental Research Online (HERO)

HERO ID

4141487

Reference Type

Journal Article

Title

Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4

Author(s)

Short, DM; Lyon, R; Watson, DG; Barski, OA; Mcgarvie, G; Ellis, EM

Year

2006

Is Peer Reviewed?

1

Journal

Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333

Volume

210

Issue

1-2

Page Numbers

163-170

Language

English

PMID

16289176

DOI

10.1016/j.taap.2005.09.01

Web of Science Id

WOS:000234452900023

URL

https://www.proquest.com/scholarly-journals/metabolism-trans-muconaldehyde-cytotoxic/docview/67580185/se-2?accountid=171501
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Abstract

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 Vmax of 2141+/-500 nmol/min/mg and a Km of 11+/-4 microM. This enzyme was inhibited by pyrazole with a KI of 3.1+/-0.57 microM. 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 Vmax of 115 nmol/min/mg and a Km of 15+/-2 microM and was not inhibited by pyrazole.

Keywords

Aldehydes; muconaldehyde; 3249-28-3; Alcohol Dehydrogenase; EC 1.1.1.1; Akr1a1 protein, mouse; EC 1.1.1.2; Aldehyde Reductase; EC 1.1.1.21; Benzene; J64922108F; Index Medicus; Inactivation, Metabolic; Animals; Stereoisomerism; Cloning, Molecular; In Vitro Techniques; Mice, Inbred Strains; Liver -- metabolism; Liver -- drug effects; Aldehydes -- pharmacokinetics; Alcohol Dehydrogenase -- metabolism; Aldehyde Reductase -- metabolism; Liver -- enzymology; Benzene -- metabolism