Inactivation of hepatocyte protein kinase C by carbon tetrachloride: involvement of drug's metabolic activation and prooxidant effect.
The involvement of CCl4 biotransformation mechanism in decreasing the Protein Kinase C activity has been analyzed in hepatocytes isolated from phenobarbital-pretreated rats. A significant inhibition (55%) and an almost total disappearance (87%) of the enzyme activity were observed at 15 min and at 30 min incubation with CCl4, respectively. Cell preincubation with Trolox or desferrioxamine allowed a marked whilst not complete protection of both cytosolic and particulate Protein Kinase C activity. These results show that the CCl4 reactive metabolites play a primary role in hepatocyte Protein Kinase C impairment and suggest that besides lipid peroxidation other mechanisms -possibly a derangement of Ca2+ homeostasis- may be involved in this process.
Pronzato
M A
MA
Department of Experimental Medicine and Oncology, University of Torino, Italy.
Domenicotti
C
C
Biasi
F
F
Chiarpotto
E
E
Cottalasso
D
D
Viotti
P
P
Melloni
E
E
Marinari
U M
UM
Poli
G
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D002839:Chromans; D002251:Carbon Tetrachloride; D011493:Protein Kinase C; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D010634:Phenobarbital