Zur Frage der Induzierbarkeit mikrosomaler Enzyme am Beispiel der Cumarinhydroxylierung in der Kaninchenleber

Abstract

The action of phenobarbital, 3,4-benzpyrene and coumarin on the coumarin-hydroxylating system in the liver of 3 mo. old rabbits was investigated. The liver weight, the weight and protein content of freeze-dried microsomes and the specific activity of the coumarin hydroxylation were determined and compared with controls. The ratio of the specific activity of coumarin hydroxylation and the concentration of microsomal cytochrome P-450 was measured. The specific activity of coumarin-7-hydroxylase in liver microsomes varies greatly between different rabbit strains, but within one strain, and especially amongst animals of the same litter, it is quite constant. After the administration of phenobarbital to rabbits, the liver weight increases by 40%, microsomes by 50% and the protein content of the microsomes by 20%. After the administration of 3,4-benzpyrene to rabbits, there is only a slight (about 10-20%) increase in liver weight, the microsomes increase slightly or not at all, and their protein content increases by 15%. The liver weight, the microsomes and the specific activity of the coumarin hydroxylase are not increased by coumarin. The simultaneous administration of coumarin and phenobarbital has the same effect as phenobarbital alone. The specific activity of coumarin hydroxylation in positions 3, 5, 6, 7 and 8 is not increased after the administration of phenobarbital or 3,4-benzpyrene, even when accompanied by coumarin. The specific level of microsomal cytochrome P-450 is increased 2-fold after treatment with phenobarbital and 1.7-fold after 3,4-benzpyrene. The specific level of microsomal cytochrome P-450 and the specific activity of coumarin hydroxylation do not show parallel behavior. Cytochrome P-450 which is sensitive to carbon monoxide, is therefore not a limiting factor for coumarin hydroxylation, although it takes part in this reaction.