Haloalcohols deplete glutathione when incubated with fortified liver fractions.
1. This study has examined the ability of dichloropropanols, haloalcohols and their putative metabolites to deplete glutathione when incubated with liver fractions obtained from untreated and differentially induced rats. 2. 1,3-Dichloropropan-2-ol and 2,3-dichloropropan-1-ol (0-1000 microM) both depleted glutathione in a dose-dependent manner when incubated with cofactors (NADPH generating system) and liver microsomes from the untreated rat. 3. The extent of GSH depletion was significantly enhanced when liver microsomes from the isoniazid- or isosafrole-treated rat were used. 4. Epichlorohydrin produced a moderate, dose-dependent depletion of GSH. By contrast, 1,3-dichloroacetone (identified by TLC as a metabolite of 1,3-dichloropropanol) was a potent depletor of glutathione. 5. N-acetylcysteine was less efficient than glutathione as a nucleophile trap for epichlorohydrin, 1,3-dichloroacetone or reactive metabolites derived from 1,3-dichloropropan-2-ol. 6. 1,3-Dibromopropan-2-ol and 1,4-dibromobutan-2-ol were potent depletors of GSH but 1-bromopropan-2-ol produced less GSH depletion. Both dibromoalcohols depleted GSH when incubated with dialysed cytosol derived from the livers of untreated rats. 7. The GSH depletion mediated by 1,3-dichloropropan-2-ol, 1,3-dibromopropan-2-ol, 1,4-dibromobutan-2-ol and 1-bromopropan-2-ol was inhibited by inclusion of pyridine (1 mM) or cofactor omission. 1,3-Difluoropropanol did not deplete GSH under any of the conditions examined.
Garle
M J
MJ
School of Biomedical Sciences, Medical School, Queens Medical Centre, Nottingham, UK. michael.garle@nottingham.ac.uk
Sinclair
C
C
Thurley
P
P
Fry
J R
JR
D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002728:Chlorohydrins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D020005:Propanols / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000517:alpha-Chlorohydrin / Q000031:analogs & derivatives* / Q000378:metabolism
D002728:Chlorohydrins; D016166:Free Radical Scavengers; D007527:Isoenzymes; D020005:Propanols; C033489:1,3-dichloro-2-propanol; C110243:1,3-difluoro-2-propanol; C076159:2,3-dichloro-1-propanol; D003577:Cytochrome P-450 Enzyme System; D000517:alpha-Chlorohydrin; D005982:Glutathione Transferase; D005978:Glutathione; D000111:Acetylcysteine