On the hepatotoxicity of 1,1,2,2-tetrachloroethane.
Intoxication of male and female mice with a single dose (300 or 600 mg/kg) of 1,1,2,2-tetrachloroethane (TTCE) resulted in significant decreases in cytochrome P-450 (to 58-73% of the control) and NADPH-cytochrome (P-450) c-reductase (to 29-35% of the control) in hepatic microsomes. This was accompanied by an alteration of mixed function monooxygenases stemming from the marked reduction (to 20-64% of the control) of several oxidative activities to selected substrates towards different P-450 isozymes (classes IA1, IA2, IIB1, IIE1 and IIIA). As phase II markers, epoxide hydrolase (approximately 35% loss), UDP-glucuronosyl transferase (approximately 42% loss) and to a lesser extent glutathione S-transferase (approximately 17% loss) were all affected. Also, the activity of delta-aminolevulinic (ALA) synthetase was decreased (approximately 57% of the control). On the contrary, heme oxygenase activity was increased (up to 35%) at the maximal dose tested. The decrease of P-450-function may be explained in terms of an alteration in the rate of heme biosynthesis and degradation, provoking a loss of heme content (approximately 33%) as well as of the direct inactivation of both P-450 and reductase. Because of increasing evidence on the involvement of free radical intermediates in the case of toxicity of haloalkanes, electron spin resonance spectroscopy (ESR) spin-trapping in vivo techniques were used to characterize the possible free radical species involved in the observed liver damage. The results obtained with the spin-trap N-benzylidene-2-methylpropylamine N-oxide (phenyl t-butylnitrone, PBN) provide evidence for the formation and trapping of the CHCl2CHCl free radicals. The detection of conjugated diene signals by means of second-derivative spectrophotometry, have enabled us to show that in vivo lipid peroxidation may be one of the main mechanisms responsible for TTCE hepatotoxicity.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy.
Sapigni
E
E
Mesirca
R
R
Pedulli
G F
GF
Corongiu
F P
FP
Dessi
M A
MA
Cantelli-Forti
G
G
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D004980:Ethane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice
D005609:Free Radicals; D006843:Hydrocarbons, Chlorinated; C015530:1,1,2,2-tetrachloroethane; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D004980:Ethane