Repeated derepression cycles of the glucuronolactone dehydrogenase and cytochrome P-450 in the rat liver induced by phenobarbitone administration

Abstract

Treatment of adult male rats with five doses of phenobarbitone was repeated at 4-day and monthly intervals in order to study the memory of the derepression cycles of glucuronolactone dehydrogenase and cytochrome P-450 in the liver. When the interval was 1 month, further drug treatments resulted in a similar increase of these enzyme levels and the relative liver weight, both during the second and third treatments. If the next treatment was commenced after an interval of 4 days, when the enzyme levels were still high, significantly lower cytochrome P-450 levels were observed after the third, than after the first and second treatments, and furthermore, after the third treatment the decline of cytochrome P-450 was more rapid than after the first phenobarbitone treatment. The increase and decrease of glucuronolactone dehydrogenase activity took place at a considerably slower rate than that of cytochrome P-450. After five phenobarbitone administrations there was a significant increase of cytochrome P-450 and also of glucuronolactone dehydrogenase for up to 48 hr, followed by a decrease to normal level of cytochrome P-450 in 8 days. On the eighth day glucuronolactone dehydrogenase activity was still nearly two-fold in comparison with the controls. The results indicate that successive phenobarbitone treatments do not result in any permanent memory effects in the metabolism of glucuronolactone dehydrogenase and cytochrome P-450, although if repeated with 4-day intervals a diminished inductive response was observed on the third treatment.