Comparison of the in vitro metabolisms and mutagenicities of dibenzo[a, c]anthracene, dibenzo[a, j]anthracene and dibenzo[a,j]anthracene: influence of norharman

Abstract

The comparison of the behaviour of three dibenzoanthracene (DBA) isomers, dibenzo[a,c]anthracene (DB[a,c]A), dibenzo[a,h]anthracene (DB[a,h]A) and dibenzo[a,j]anthracene (DB[a,j]A), polycyclic aromatic hydrocarbons (PAHs), whose carcinogenicity varies from very potent to apparently inactive, has been carried out. Influence of norharman (NH; 9H-pyrido[3,4-b]indol) was investigated for mutagenicity (reversion of histidine prototrophy) on Salmonella typhimurium TA 100, using 3-methylcholanthrene (3-MC)-induced rat liver microsomes or S9 (post-mitochondrial fractions). A correlation with its influence, on the in vitro metabolism of radiolabelled molecules by the same enzymatic systems, was carried out. NH enhances the mutagenicities of DB[a,c]A and DB[a,h]A which are very well known mutagenic and carcinogenic PAHs. Contrary to its two isomers, the mutagenic potency of DB[a,j]A, which is considered as a weak mutagen and not a carcinogen, is strongly inhibited by NH. The balance sheets of the in vitro metabolism by microsomal enzymes, where the conjugation is excluded, were reported with or without NH. In the presence of the latter, the amounts of remaining DBAs slightly decreased while the metabolites covalently bound to microsomal proteins strongly decreased and the amount of hydrophobic metabolites highly increased. At the same time, the HPLC elution profiles of the metabolism pathways of the three DBAs are found to be modified in a similar way by NH: some of the metabolites are highly enhanced, and for all three DBAs, a tetraol, not detectable in the absence of NH, emerges. The results are discussed with regard to possible effects of NH.