The effect of sucrose on the induction of hepatic and peripheral insulin resistance is well-documented. Studies show that, although oral administration of glucose does not significantly decrease total hepatic microsomal cytochrome P450 content, it causes an increase in cytosolic protein and in microsomal phospholipid and fatty acid content. In this study we examined the effects of a chronic high sucrose diet (HSD) on liver enzyme activity. Male Fisher 344 weanling rats were randomly assigned to a control diet (0% sucrose by calories, n = 10) or a diet in which starch was replaced by sucrose (65% sucrose, by calories, n = 10) for 90 days. The effects of HSD on weight gain, liver weight, hepatic microsomal cytochrome P450 (CYP450) content and glutathione-S-transferase (GST) activity were measured and compared with those fed standard lab chow. A small but statistically significant decrease in body weight (g) was seen in the sucrose-fed rats after day 50. Liver GST activity (nmol/mg protein/min) at the end of 90 days was decreased in animals maintained on HSD compared to those on the control diet, (181.7 +/- 8.0, 234.7 +/- 5.5), respectively. The liver weight and total CYP450 content in the two diet groups were not significantly different. The ratios of liver weight to body weight at the end of 90 days suggested that the livers of the HSD-fed animals were larger per gram of body weight. In addition, rats on the HSD had significantly smaller amounts of liver CYP450 1A1 and 3A2 than the rats on the control diet. These results suggest that a HSD may alter the hepatic enzyme activity which may affect the metabolism of substrates for these enzyme systems.