Induction of drug-metabolizing enzymes of rat liver by derivatives of coumarin

Abstract

The ability of coumarin and 35 structurally related compounds to induce coumarin 3-hydroxylase was examined in the liver of the rat. After seven daily oral doses of 1 mmole/kg of the test compound, the hydroxylase activity with coumarin or 4-methylcoumarin as substrate was increased 13- to 14-fold by 8-(2″-butenyloxy-3″-methyl)-furo-(2′:3′–6:7) coumarin; 4- to 8-fold by 4-methylcoumarin; 6-fold by 6-acetyl-4,8-dimethyl-7-hydroxycoumarin; 2- to 5-fold by 7,8-dihydroxy-4-methylcoumarin; 2- to 3-fold by 6,7-dihydroxy-4-methylcoumarin, 7-hydroxy-4-methylcoumarin, 4,8-dimethyl-7-hydroxycoumarin, 3-isopropyl-7-methoxy-4-methyl coumarin, 3-chloro-7-methoxy-4-methylcoumarin, and 3-carboxycoumarin. Nearly all enzyme inducers contained the 4-methyl substituent. 4-Methylcoumarin and 6,7-dihydroxy-4-methyl coumarin elicited a greater induction on the hydroxylation of 4-methylcoumarin than on that of coumarin. The other coumarin derivatives brought about no consistently greater effect on either hydroxylase. No correlation was found between the induction effect and the lipid solubility of the inducer. 4-Methylcoumarin exerted a greater induction effect on coumarin 3-hy droxylase than on nitroanisole or codeine demethylase and hexobarbitone or butylated hydroxy toluene oxidases. Other known enzyme inducers (hexobarbitone, 17-methyltestosterone, and 20-methylcholanthrene) also increased hydroxylase activity in a manner comparable to that of 4-methylcoumarin.