Pathways of trans,trans-muconaldehyde metabolism in mouse liver cytosol: reversibility of monoreductive metabolism and formation of end products.
The metabolism of trans,trans-muconaldehyde (MUC), a hematotoxic agent which is a presumed in vivo metabolite of benzene, was studied in mouse liver cytosol. MUC was incubated for 30 min at 37 degrees C with mouse liver cytosol (from CD-1 mice) supplemented with NAD+ and the products were analyzed by reverse phase HPLC. Two products were detected in addition to the previously identified acid-aldehyde 6-oxo-trans,trans-2,4-hexadienoic acid (COOH-M-CHO) and the diacid trans,trans-muconic acid (COOH-M-COOH). Based on the molecular weight (112) obtained by thermo-spray LC-mass spectrometry and the absorbance maximum (269 nm), one of the products was identified as the aldehyde-alcohol 6-hydroxy-trans,trans-2,4-hexadienal (CHO-M-OH). The second product was identified as 6-hydroxy-trans,trans-2,4-hexadienoic acid (COOH-M-OH) by coelution with authentic standard, the fragmentation pattern obtained by electron impact mass spectrometry and the absorbance maximum (258 nm). Time course and concentration dependency studies indicate that COOH-M-OH and COOH-M-COOH are end products of MUC metabolism while CHO-M-OH, and COOH-M-CHO, the initially formed mono-reduction and mono-oxidation products, respectively, are the intermediates leading to these end products. The metabolite COOH-M-OH is formed mainly by oxidation of CHO-M-OH and to a much lesser extent by reduction of CHO-M-COOH, whereas COOH-M-COOH is formed solely by oxidation of COOH-M-CHO. The reduction of MUC to CHO-M-OH is reversible, whereas oxidation to COOH-M-CHO is not. The compound CHO-M-OH is not only oxidized to COOH-M-OH by oxidation of the aldehyde functional group, but is also converted back to MUC by oxidation of the alcohol functional group.
Zhang
Z
Z
Joint Graduate Program in Toxicology, Rutgers University/UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854.
Kline
S A
SA
Kirley
T A
TA
Goldstein
B D
BD
Witz
G
G
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D000447:Aldehydes; C034476:muconaldehyde