Abstract
The effects of a number of naturally occurring anutrients on various hepatic drug-metabolizing enzyme activities have been studied in rats. These enzyme activities include aromatic hydroxylation (biphenyl-4- and -2-hydroxylases), reduction (p-nitrobenzoic acid reductase), conjugation (4-methylumbelliferone glucuronyl transferase), cytochrome P-450 and cytochrome b[5]. The groups of anutrients studied were terpenoids, alkaloids, flavonoids, esters, ethers, and methylenedioxyaryl compounds. Some of these compounds have shown no immediate effect on the drug-metabolizing enzymes, others have shown a modest induction of some of the above enzymes to the order of 10-15%, a few compounds have shown inhibition. One of the terpenoids, beta-ionone, and two of the methylenedioxyphenyl compounds, safrole and iso-safrole, have exhibited marked induction of all the parameters studied. These three compounds have also been found to decrease the liver glycogen content and to enhance the glucuronic acid pathway of carbohydrate metabolism manifested by an increased excretion of ascorbic acid in the urine. Differences in the enzyme inductive effects of beta-ionone, safrole and iso-safrole dependent on species, age and sex, have also been studied. The enzyme inductive effects of these three compounds have been compared qualitatively and quantitatively to those of phenobarbitone and 3-methylcholanthrene, potent representatives of the two known groups of inducers. The mechanisms of induction of the hepatic drug-metabolizing enzymes by these naturally occurring anutrients have been studied, and in this connection the inhibitors of protein synthesis, actinomycin D (m-RNA synthesis) and thioacetamide (m-RNA release), and of haeme synthesis, 3-amino-1,2,4-triazole, have been used. Other studies have been made, using [3]H-leucine on the rates of synthesis and turnover of proteins in the microsomal and other sub-cellular fractions of the liver. From these experiments it has been shown that beta-ionone, like phenobarbitone, results in a type of enzyme induction which is very largely dependent on the DNA-directed synthesis of new enzyme proteins. Safrole and iso-safrole, on the other hand, are like 3-methylcholanthrene, and result in a type of enzyme induction which is in part dependent on the synthesis of new enzyme proteins and partly results from changes in the conformation of the enzyme or from alterations of its membrane environment. Pretreatment with safrole or iso-safrole has been shown to result in the appearance of a new hepatic microsomal haemoprotein which is normally not detectable in tissue homogenates of untreated animals.