Quantitative relationships between the LOEL values for hepatotoxicity and cytochrome P450-inhibitory activity of chemical substances

Abstract

Repeated-dose toxicity (RDT) study is important for evaluating the safety of chemical substances, but the development of alternative methods is strongly needed. Recent studies indicate that mechanism-based in vitro assays are useful for predicting RDT. Recently, we found that the inhibition of some cytochrome P450 (P450), including CYP1A1, may induce hepatotoxicity. In this study, we examined the quantitative relationship between P450-inhibitory activity and the LOEL for hepatotoxicity of chemical substances to clarify whether the P450 inhibition test is useful for the quantitative prediction of hepatotoxicity. We selected 326 compounds for which RDT study results were available from the Hazard Evaluation Support System Integrated Platform. Their inhibitory activity against rat P450 (CYP1A1/1A2/2B1/2C6/2D1/3A2) was evaluated at three concentrations (0.1, 1.0, and 10μM) using recombinant enzymes and luminescent substrates. The relationship between the sum of inhibitory activity at the three concentrations and LOEL for five hepatotoxicity-related endpoints was examined. The results indicated that compounds with higher inhibitory activity tended to show lower LOEL in some combinations of hepatotoxicity and P450s (e.g., cell death/inflammation and CYP1A1/1A2/2B1; hepatic dysfunction and CYP1A1/1A2/2D1; bile duct injury and CYP1A1/1A2; hypertrophy and CYP1A1/1A2/2B1/2C6/2D1/3A2, dyslipidemia and CYP2B1), The results suggest that inhibitory activity values are useful for quantitative prediction of hepatotoxicity in certain compound groups.