In vitro and in vivo metabolism of trans,trans-muconaldehyde, a hematotoxic microsomal metabolite of benzene
Trans,trans-muconaldehyde (MUC) has been previously identified in the authors laboratory as a hematotoxic microsomal ring-opened metabolite of benzene. Trans,trans-muconic acid (MA), a known urinary metabolite of benzene, has been proposed to be a metabolite of MUC. The present studies were undertaken to determine (1) whether MUC is a precursor of urinary MA and (2) whether differences in oxidative metabolism of MUC might account for differences in benzene sensitivity among DBA and C57Bl mice. The in vivo metabolism of MUC was compared among DBA/2J and C57Bl/63 which have known differences in acetaldehyde metabolism. The present studies demonstrate that purified yeast aldehyde dehydrogenase (ALDH) in the presence of NAD{sup +} metabolizes MUC based on the production of NADH measured spectrophotometrically at 340 nm. In similar experiments, cytosol prepared from the liver of DBA/2J and C57Bl/6J mice and supplemented with NAD{sup +} was also found to metabolize MUC. Using TLC and HPLC techniques, a product with intermediate polarity compared with that of the dialdehyde (MUC) and the diacid trans,trans-muconic acid (MA) standards was detected in both the ALDH and mouse liver cytosol incubation mixtures. Mass spectral analysis and functional group tests support a structural assignment of OHC-CH{double bond}CH-CH{double bond}CH-COOH for this intermediate. This intermediate inhibited yeast ALDH. In the presence of liver cytosol supplemented with NAD{sup +} this intermediate was further metabolized to MA. This monoacid is a major metabolite of MUC in vitro. An alternate mechanism for the oxidative metabolism of MUC in may involve oxidases. In the presence of ruptured mouse liver mitochondria or purified milk xanthine oxidase, MUC is metabolized to the monocarboxylic acid-aldehyde and MA as determined by HPLC.
- Research Organization:
- Rutgers-the State Univ., New Brunswick, NJ (USA)
- OSTI ID:
- 5756914
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ALDEHYDES
METABOLISM
OXIDOREDUCTASES
ENZYME ACTIVITY
BENZENE
IN VITRO
IN VIVO
LIQUID COLUMN CHROMATOGRAPHY
LIVER
METABOLITES
MICE
MICROSOMES
MITOCHONDRIA
NAD
NADH2
YEASTS
ANIMALS
AROMATICS
BODY
CELL CONSTITUENTS
CHROMATOGRAPHY
COENZYMES
DIGESTIVE SYSTEM
ENZYMES
EUMYCOTA
FUNGI
GLANDS
HYDROCARBONS
MAMMALS
MICROORGANISMS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
PLANTS
RIBOSOMES
RODENTS
SEPARATION PROCESSES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550501 - Metabolism- Tracer Techniques