In vivo studies on halogen compound interactions. IV. Interaction among different halogen derivatives with and without synergistic action on liver toxicity.
The liver toxicity of several halogen compound mixtures have been tested. The compounds were selected on the basis of their metabolic pathways: carbon tetrachloride (CT) and trichlorobromomethane (TCBM) undergo a dehalogenation via P450-dependent enzyme system, 1,2-dichloroethane (DCE) and 1,2-dibromoethane (DBE) are mainly conjugated with the cytosolic glutathione (GSH) by means of the GSH-S-transferase. The mixture TCBM+DBE shows a more than additive action on lipid peroxidation and liver necrosis. TCBM, like CT, reduces the hepatic level of GSH-S-transferase, increasing the amount of DBE available for cytochrome P450-dependent metabolism, with the production of toxic metabolites. Thus, the behavior of the mixture TCBM+DBE is very similar to that of the mixture CT+DBE, previously reported. Mixtures composed of CT+TCBM and DCE+DBE do not show any synergistic effect on liver toxicity. The results allow one to conclude that the toxicity of mixtures of halogen compounds can be partly predicted on the basis of their metabolic pathways. When the metabolism is quite different, a synergistic toxicity can occur if one pathway interferes with a detoxification mechanism of the other compound. If the two metabolisms are very similar they produce, at most, an additive toxicity.
Danni
O
O
Istituto di Patologia Generale, Sassari, Italy.
Aragno
M
M
Tamagno
E
E
Ugazio
G
G
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001975:Bromotrichloromethane / Q000633:toxicity*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015946:Ethylene Dibromide / Q000633:toxicity*; D005025:Ethylene Dichlorides / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains
D005025:Ethylene Dichlorides; D015946:Ethylene Dibromide; C024565:ethylene dichloride; D002251:Carbon Tetrachloride; D007064:L-Iditol 2-Dehydrogenase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001975:Bromotrichloromethane