Comparison of the effects of the hypolipidaemic agents ICI 53072 and clofibrate with those of phenobarbitone on liver size, blood flow and DNA content in the rat

Abstract

1 The effects of the hypolipidaemic agents ICI 53072 and clofibrate on cardiac output and its distribution to the hepatosplanchnic bed were determined by the use of radioactive microspheres in the rat. The effects of these agents on hepatic DNA content were compared with those of phenobarbitone. Also the effects of ICI 53072 on hepatic microsomal enzymes and bile flow were determined together with the effects of phenobarbitone. 2 ICI 53072 and clofibrate both increased liver size and liver blood flow. A daily dose of 25 mg kg⁻¹ ICI 53072 for 5 days increased liver weight by 55% and liver blood flow by 43%, the latter by enhancing the proportion of cardiac output passing to the hepatosplanchnic bed. The increased liver blood flow with clofibrate (480 mg kg⁻¹ daily for 5 days) was the result of greater cardiac output but the change (35%) was half the increase in liver weight. 3 Phenobarbitone (80 mg kg⁻¹ daily for 5 days) produced a fall in DNA content per unit mass of liver but no change in hepatic DNA relative to body weight. ICI 53072 (25 mg kg⁻¹ daily) increased hepatic DNA relative to body weight but by a lesser extent than it increased liver weight as a proportion of body weight; hence DNA content per unit mass of liver decreased. Clofibrate at three dose levels increased hepatic DNA relative to body weight but only one dose significantly decreased DNA content as a proportion of liver weight. 4 Phenobarbitone (80 mg kg⁻¹ daily) increased bile flow whereas ICI 53072 (25 mg kg⁻¹ daily) had no effect. Both treatments increased hepatic cytochrome P450 content and cytochrome c reductase activity. 5 It is concluded that phenobarbitone increases liver size by hepatocyte enlargement rather than cellular proliferation but that the hepatomegaly produced by the hypolipidaemic agents, at least at some doses, is due to a mixture of both processes. 6 It is further concluded that there is no simple relationship between the mechanism of hepatic enlargement resulting from drug treatment and changes in liver blood flow.