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Current Topics in Toxicology   Volumes    Volume 4 
Involvement of CYP1A1 and CYP2E1 in N, N-dimethyldithiocarbamate-mediated hepatocellular injury in rats: a possible role of oxidative stress
Ramesh R. Dalvi, Prasad S. Dalvi, Leonard H. Billups
Pages: 31 - 38
Number of pages: 8
Current Topics in Toxicology
Volume 4 

Copyright © 2007 Research Trends. All rights reserved

This study was conducted to examine time-dependent effect of the fungicide dimethyl-dithiocarbamate (DMDC) on cytochrome P450 (CYP) isoenzymes 1A1 and 2E1 induced by 3-methylcholanthrene (3-MC) and isoniazid (INH), respectively, and to determine if there is a correlation between DMDC interaction with the CYPs and liver injury. DMDC administered i.p. at a low dose of  0.5 mmol/kg produced  a significantly higher inhibition of CYP1A1 in normal rats at 3 h after treatment than that in rats induced with 3-MC. However, the restoration of CYP1A1 activity was near complete in normal rats at 24 h following DMDC administration. On the other hand, DMDC inhibited CYP2E1 activity significantly more in INH-induced rats than in normal rats at 3 and 24 h after DMDC treatment.  But the inhibition of induced CYP2E1 activity remained markedly depressed even at 24 h following DMDC administration. Furthermore, this inhibition of CYP2E1 in induced rats was also accompanied by a significant elevation of serum ALT activity indicative of liver damage confirmed by histological evaluation. Measurement of lipid peroxidation and reactive oxygen species (ROS) in hepatic microsomes from normal and induced rats treated with DMDC suggested a possibility of microsomal oxidative stress being present significantly more in INH-induced rats than any other groups. All together, these studies demonstrate that DMDC is a stronger inhibitor of INH-inducible CYP2E1 than 3-MC-inducible CYP1A1, and the modest hepatotoxic effects caused by the low dose of DMDC seen only in INH-induced rats may be jointly produced by DMDC metabolism and prooxidant characteristics of the induced CYP2E1 via microsomal oxidative stress.
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