BIOALKYLATION OF BENZ(A)ANTHRACENE: IMPLICATIONS FOR CARCINOGENESIS

Abstract

Previous studies on the metabolic activation of unsubstituted polycyclic aromatic hydrocarbons have largely focused on the formation of oxidation products as a result of reaction of the parent hydrocarbon with microsomal enzymes. These products of reaction have included both epoxide as well as a diol epoxide metabolites. In addition, formation of quinones as well as hydroxyl substituted derivatives of various polycyclic aromatic hydrocarbons have been investigated as metabolic endpoints. Several studies have taken place illustrating the formation of these metabolites, as well as the formation of biologically relevant adducts in a variety of animal models as well as cell culture preparations. Although these metabolic products have been widely characterized and studied in a variety of systems, there have been limited studies characterizing the formation of methyl substituted derivatives of unsubstituted aromatic hydrocarbons, and the subsequent formation of hydroxyalkyl derivatives of various compounds. The present study investigates the formation of both alkyl and hydroxyalkyl substituted derivatives of the unsubstituted polycyclic aromatic hydrocarbon benz(a)anthracene in preparations of rat liver cytosol fortified with S-adenosyl-L-methionine. The results demonstrate that methylated derivatives are formed as metabolic products, and that the identity of these products are both the 7-methybenz(a)anthracene and 7,12-dimethylbenz(a)anthracene. These results confirm that aromatic hydrocarbons undergo biological substitution reactions at specific centers of reactivity of the unsubstituted molecule yielding bioalkylated derivatives.

Keywords:

• Carcinogen
• benz(a)anthracene
• carcinogen
• metabolism
• methylation

This article is presented in honor of Dr. James W. Flesher for over 50 years of work in the field of polycyclic aromatic hydrocarbons. His inspiration for the history, chemistry, and structure-activity relationships among this series of compounds continues to be an inspiration for ongoing scientific endeavors.