The effect of bromobenzene and 3,4-benzpyrene on the metabolism of radioactive L-cystine.

The detoxication of aromatic hydrocarbons and their halogen derivatives has been studied for many years. It has been established that these compounds undergo the biochemical reactions of oxidation to dihydrodihydroxy compounds, phe nols, and quiñones;of oxidative ring scission to form carboxylic acids; and of conjugation with cysteine to form mercapturic acids.1 With the dis covery of the carcinogenic activity of certain polycyclic aromatic hydrocarbons, interest in the me tabolism of aromatic hydrocarbons has been fur ther stimulated. Some of the predictable detoxica tion products such as the phenols and quiñonesof 3,4-benzpyrene (2, 3) and 1,2,5,6-dibenzanthracene (1) have been isolated. Recently, Heidelber ger, Kirk, and Perkins (11) have demonstrated the oxidative fission of some of the rings of dibenzanthracene. The isolation of mercapturic acids from admin istered carcinogenic hydrocarbons has never been accomplished. Nevertheless, the concept of the participation of sulfur amino acids in the metab olism of carcinogenic hydrocarbons has persisted. Haddow, Scott, and Scott (9) showed that 1,2,5,6dibenzanthracene, 1,2,5,6-dibenzacridine, and 3,4benzpyrene produced immediate and long-con tinued reduction in the growth of rats. White and White (14) found that 20-methylcholanthrene and benzpyrene produced an inhibition of growth in rats and suggested that, similar to bromobenzene, these compounds were causing a cystine deficiency through mercapturic acid formation. Crabtree (4) found no change in the neutral sulfur of the urines of mice painted with benzpyrene or dibenzanthracene. He concluded that mercapturic acids ac* This work was supported by a grant from the American Cancer Society upon recommendation by the Committee on Growth of the National Research Council. t A preliminary report of this work was presented to the American Society of Biological Chemists, Detroit, April 21, 1949. Received for publication, September 9, 1For a review of the metabolism of aromatic hydrocarbons, see Williams, R. T., Detoxication ilechanisms. New York: Wiley & Sons, Inc., 1947. counted for no major amounts of the elimination products of these hydrocarbons. However, since nonspecific disturbances in sulfur metabolism re duced the rate of tumor induction by the carcino gens, he retained the hypothesis that a primary ac tion of carcinogens is their combination with sulfhydryl groups in the cell. This point of view was reiterated by Elson, Goulden, and Warren (5), who studied the sulfur partition in urine following the administration of polycyclic hydrocarbons. They found no increase in neutral sulfur corre sponding to mercapturic acid formation after the administration of 3,4-benzpyrene or 1,2,5,6-dibenzanthracene. although profound inhibition of growth occurred. Sulfur-containing proteins in ex cess of the amount needed to permit mercapturic acid formation were fed. With diets containing 20 per cent protein, there was some protection against growth inhibition, but it was not necessarily pro vided by sulfur amino acids (6, 7). Addition of cystine to a 5 or 10 per cent casein diet failed to prevent growth inhibition. The action of the two hydrocarbons, therefore, could not be attributed to a simple deprivation of the organism's require