Abstract
| Language | English |
|---|---|
| Pages | 163-170 |
| Number of pages | 7 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 210 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - 2006 |
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Keywords
- benzene
- trans-muconaldehyde
- alcohol dehydrogenase
- bioscience
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Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4. / Short, D.M.; Lyon, R.C.; Watson, D.G.; Barski, O.A.; McGarvie, G.; Ellis, E.
In: Toxicology and Applied Pharmacology, Vol. 210, No. 1-2, 2006, p. 163-170.Research output: Contribution to journal › Article
TY - JOUR
T1 - Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4
AU - Short, D.M.
AU - Lyon, R.C.
AU - Watson, D.G.
AU - Barski, O.A.
AU - McGarvie, G.
AU - Ellis, E.
PY - 2006
Y1 - 2006
N2 - 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 μM. This enzyme was inhibited by pyrazole with a KI of 3.1 ± 0.57 μM. 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 μM and was not inhibited by pyrazole.
AB - 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 μM. This enzyme was inhibited by pyrazole with a KI of 3.1 ± 0.57 μM. 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 μM and was not inhibited by pyrazole.
KW - benzene
KW - trans-muconaldehyde
KW - alcohol dehydrogenase
KW - bioscience
UR - http://dx.doi.org/10.1016/j.taap.2005.09.017
U2 - 10.1016/j.taap.2005.09.017
DO - 10.1016/j.taap.2005.09.017
M3 - Article
VL - 210
SP - 163
EP - 170
JO - Toxicology and Applied Pharmacology
T2 - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1-2
ER -