Liver response tests. III. Liver enlargement and stimulation of microsomal processing enzyme activity

Abstract

In female rats given butylated hydroxytoluene (BHT; 3,5-di- tert-butyl-4-hydroxytoluene) by stomach tube (500 mg/kg daily for 84 days) liver enlargement was associated with increased activity of the microsomal processing (drug metabolizing) enzymes aminopyrine demethylase, hexobarbitone oxidase and nitroanisole demethylase; a similar effect was observed in mice. Rats treated with butylated hydroxyanisole (BHA; 3- tert-butyl-4-hydroxyanisole) had enlarged livers, but no change in processing enzyme activities was observed. Investigation of the time course and dose-response relationship of the BHT effect revealed a close correlation between increased relative liver weight (RLW), enhanced processing enzyme activity and mobilization of stored BHT from abdominal fat. In rats of both sexes given BHT as above for up to 21 days, RLW and processing enzyme activities were significantly raised by the second day, by which time BHT content of fat had attained values of 230 ppm in females and 162 ppm in males. On days 3 and 4, RLW and enzyme activities continued to rise but the BHT content of fat fell to about 100 ppm in both sexes, remaining at this level until the end of treatment. In female rats given BHT, the threshold for increases in RLW and processing enzyme activity lay between 25 and 75 mg/kg daily for 7 days. At this threshold a change took place in the relationship between dose and level in body fat: up to 25 mg/kg daily, the BHT content of fat rose in proportion to the dose, reaching 19 ppm; but, with increasing dosage above the threshold, the rate of increase of BHT in fat was reduced, so that the level was only 97 ppm at a dose of 500 mg/kg daily. The significance of these findings is discussed in relation to the assessment of safety-in-use. It is concluded that liver enlargement induced by BHT is a physiological response.