The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference

Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.