Species- and sex-related differences in metabolism of trichloroethylene to yield chloral and trichloroethanol in mouse, rat, and human liver microsomes.
Trichloroethylene (TRI) has been shown to cause a variety of tumors, particularly in mouse liver and lung and rat kidney. However, a clear association between exposure to TRI and cancer development in humans has not been established. Because TRI metabolism by cytochrome P450s has been implicated in the mechanisms of TRI-induced carcinogenicity in mice, the purpose of the present study was to characterize the kinetics of TRI oxidation in male and female mouse, rat, and human liver microsomes to possibly allow for a better assessment of human risk. Methods were developed to detect and quantitate chloral, trichloroethanol, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, glyoxylic acid, and oxalic acid, known TRI metabolites in rodents or humans. However, only chloral and its further metabolite, trichloroethanol, were consistently detected in the various liver microsomes in the presence of NADPH. Chloral was the major metabolite detected, and its levels were species- and sex-dependent; the amounts of trichloroethanol detected were also species- and sex-dependent but never exceeded 15% of total metabolites. Double-reciprocal plots of metabolite formation with male and female rat and human liver microsomes indicated biphasic kinetics, but this trend was not observed with microsomes from male or female mouse liver. The Vmax data are consistent, with male and female mice being more susceptible to TRI-induced liver carcinogenicity than male rats. However, the Vmax/Km ratios in male and female rat liver microsomes, in comparison with the male mouse liver microsomes, did not correlate with tumor incidences in these tissues. Furthermore, as only two out of six human liver samples examined exhibited Vmax/Km ratios similar or higher than the ratio obtained with male mouse liver, humans may vary in their toxic response after TRI exposure.
Department of Comparative Biosciences, University of Wisconsin School of Veterinary Medicine, Madison, WI 53706, USA.
A A
AA
Elfarra
R J
RJ
Krause
A R
AR
Last
L H
LH
Lash
J C
JC
Parker
D000085:Acetates / Q000378:metabolism; D000818:Animals; D002697:Chloral Hydrate / Q000031:analogs & derivatives* / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000378:metabolism; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006038:Glyoxylates / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism / Q000494:pharmacology; D010070:Oxalates / Q000378:metabolism; D019815:Oxalic Acid; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D012997:Solvents / Q000378:metabolism*; D013045:Species Specificity; D014241:Trichloroethylene / Q000378:metabolism*
D000085:Acetates; D006038:Glyoxylates; D010070:Oxalates; D012997:Solvents; D014241:Trichloroethylene; D002697:Chloral Hydrate; D009249:NADP; C006972:chloroacetic acid; D005023:Ethylene Chlorohydrin; D019815:Oxalic Acid; D003999:Dichloroacetic Acid; C005849:2,2,2-trichloroethanol; C021100:trichloroacetaldehyde; C031150:glyoxylic acid