Correlations between common tests for assessment of liver damage: Indices of the hepatoprotective activity of promethazine in carbon tetrachloride hepatotoxicity

Abstract

The effects of promethazine (PM) on different aspects of the hepatotoxic action of CCl₄ in the rat were investigated with the objective of finding rapid and reliable indicators of hepatoprotective effects. The study was based on definitive histological assessment of liver damage caused by CCl₄ in the presence and absence of PM: PM (78 μmol kg⁻¹, i.p.) protected against CCl₄‐induced hepatic necrosis 24 h after a low dose of CCl₄ (1.3 mmol kg⁻¹) but not against a higher dose (13.0 mmol kg⁻¹). The large increases in plasma activities of GOT, GPT and LDH produced by dosing with CCl₄ were partially inhibited by the administration of PM. PM and CCl₄ caused a synergistic and long‐lasting decrease in body temperature (2–3°C for 8–10 h). Modifying the toxicity with PM, together with a low dose of CCl₄, helped to minimize secondary effects of CCl₄, to clarify the sequence of toxic events, and to assess the sensitivity of some standard tests of hepatotoxicity. Simultaneous measurement of over 20 commonly used biochemical screening tests in individual animals 3 or 6 h after treatment permitted direct correlation of a wide variety of concentrations, activities and effects. For example, liver CHCl₃ concentrations (as a measure of CCl₄ metabolism) correlate strongly with increases in diene conjugation of microsomal lipids (as a measure of CCl₄‐induced lipid peroxidation); malonaldehyde production appears to be less sensitive as a measure of lipid peroxidation in vivo than diene conjugation. The changes induced in each parameter and the correlations between them are discussed with reference to the overall nature of the hepatotoxic reaction and its modification by PM.