Toxicologic implications of the metabolism of thiram, dimethyldithiocarbamate and carbon disulfide mediated by hepatic cytochrome P450 isozymes in rats

Abstract

These studies were conducted to identify the P450 isozymes participating in the metabolism of thiram (tetramethylthiuram disulfide) and its two metabolites DMDC (dimethyldithiocarbamate) and CS 2 (carbon disulfide), and to establish the relationship between the P450-mediated metabolism of these compounds and their possible hepatotoxic effects. These compounds were individually administered i.p. to normal rats at two equimolar doses (0.1 and 0.5 mmol/kg).The animals were sacrificed at 3 h after treatment to identify the inhibited isozymes, and at 24 h to determine the hepatic damage. The results indicated that only the higher dose of thiram inhibited the activities of CYP1A1 and 2B1 significantly at 3 h after treatment whereas CYP2E1 was depressed by both doses and CYP3A2 remained unaffected by either dose. At 24 h after treatment, higher dose of thiram significantly depressed only the CYP1A1 and 2E1 activities. Both CYP1A1 and 2E1 were inhibited by higher dose of DMDC, but there was no significant inhibition of CYP2B1 or 3A2 by DMDC at 3 h following treatment. Unlike thiram, DMDC did not affect the activity of any of the CYP isozymes at 24 h after treatment. At 3 h post-treatment, although the higher dose of CS 2 significantly inhibited CYP1A1, 2B1, 2E1, and 3A2, the lower dose decreased the activities of only CYP1A1, 2B1, and 2E1. On the other hand, CS 2 increased the activities of CYP1A1, 2B1, and 2E1 at 24 h following treatment with no effect on CYP3A2. It is further observed from the results that only thiram at higher dose caused liver damage as measured by a significant increase in the activities of SDH and ALT. The results suggest that CYP1A1, 2B1, and 2E1 appear to be mostly involved in the metabolism of these compounds, and among them only thiram is hepatotoxic.