Depression of glutathione content, elevation of CYP2E1-dependent activation, and the principal determinant of the fasting-mediated enhancement of 1,3-dichloro-2-propanol hepatotoxicity in the rat.
The influence of fasting (18 hours) on the hepatotoxicity of 1,3-dichloro-2-propanol (1,3-DCP) and on various hepatic parameters has been assessed in the rat. Fasting produced an enhancement of the hepatotoxicity which was associated with alterations in a variety of hepatic parameters when measured relative to protein content, most notably glutathione (GSH) levels (decrease) and CYP2E1-mediated enzyme activity (increase), two parameters previously identified as being important determinants to the toxicity. Fasting also decreased the liver weight normalized to body weight. When this was taken into account, total liver CYP2E1-mediated enzyme activity was not significantly altered whereas the total liver GSH level was markedly reduced following fasting. These results imply that the reduction in hepatic GSH is the principal determinant of the enhanced susceptibility to 1,3-DCP hepatotoxicity following fasting.
Fry
J R
JR
School of Biomedical Sciences, Medical School, Queen's Medical Centre, Nottingham, UK.
Sinclair
D
D
Piper
C H
CH
Townsend
S L
SL
Thomas
N W
NW
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004789:Enzyme Activation; D005215:Fasting / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests; D000517:alpha-Chlorohydrin / Q000031:analogs & derivatives* / Q000633:toxicity
D011506:Proteins; C033489:1,3-dichloro-2-propanol; D000517:alpha-Chlorohydrin; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione