| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 99 === Backgrounds and Aims: Cytochrome P450 2E1 (CYP2E1) could play an important role in the pathogenesis of isoniazid (INH)-induced hepatotoxicity. The aim of this study was to prove the concept that apply this mechanism using a CYP2E1 inhibitor, disulfiram (DSF), to protect against INH-induced hepatotoxicity.
Methods: The hepatotoxic dose of INH was 150 mg/kg/day. DSF 100 mg/kg/day was selected as a model drug to prevent hepatotoxicity induced by INH. All of the drugs were administered intraperitoneally (1 ml/kg/day) over a period of 21 days in male Sprague-Dawley rats. Plasma 8-iso- prostaglandin F2α (8-iso-PGF2α) was chosen as a marker of hepatic oxidative stress; galactose single point (GSP) method and galactose elimination capacity (GEC), as quantitative measurements of liver function, and histopathologic features of the respective liver specimens besides aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to assess the hepatotoxicity and hepatoprotection caused by INH and DSF, respectively.
Results: The hepatic injuries exposed to INH alone were evidenced by significant increases of CYP2E1 activity from 684 ± 67 to 1570 ± 286 pmol/min/mg (p < 0.001); the values of 8-iso-PGF2α were from 111 ± 16 to 151 ± 27 pg/ml (p < 0.001) and GSP values were from 384 ± 69 to 565 ± 87 g/ml (p < 0.001), and all could be compromised by the pre- administration of DSF (significantly reduced of CYP2E1 activity from 1570 ± 286 to 427 ± 58 pmol/min/mg, 8-iso-PGF2α values reduced from 151 ± 27 to 126 ± 20 pg/ml and GSP values reduced from 565 ± 87 to 449 ± 45 g/ml, respectively). Electron microscopic examination of liver histology confirmed the above mentioned phenomenum.
Another study in GSP application: The hyperglycemia effect studies in rats were divided into four groups, as follows: (1) normal control (NC), (2) streptozotocin-induced diabetes (DM), (3) carbon tetrachloride–induced hepatotoxicity (CCl4), and (4) streptozotocin-induced diabetes with CCl4-induced hepatotoxicity (DM + CCl4).
Methods: The serum glucose levels in the diabetic groups (DM and DM + CCl4) were significantly increased compared with NC and CCl4 groups (p ＜0.001). A significant increase in hepatic activities of AST and ALT was observed in CCl4-treated groups (CCl4 and DM + CCl4) compared with NC and DM groups (p ＜0.001). In comparison with NC group, the values of GSP and GEC in diabetic groups (DM and DM + CCl4) were significantly reduced (p ＜0.001) and increased (p ＜0.01), respectively.
Conclusions (1): The amelioration of INH-induced hepatotoxicity by the model drug, DSF was proven using 8-iso-PGF2α, GSP, GEC and relatively normal morphology and liver histology in rats. The possible mechanism was confirmed by the significant decrease of CYP2E1 activity. CYP2E1 inhibitors with minimum toxicity may be a useful adjuvant to any CYP2E1 induced drug’s hepatotoxicity, such as anti-tuberculosis chemotherapy, INH, Rifampin etc. (2) : GSP had highly significant correlations with GEC (p ＜0.001). These results suggest that galactose metabolism tests-as quantitative parameters of liver function-should be interpreted with caution in the condition of a significant hyperglycemia.
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