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.

The Gulf Oil Spill

“…However, specific methylated phenanthrenes, which direct the metabolic fate there is a substantive body of evidence that confirms the hypothesis implicating the formation of bay region diol epoxides as the major mechanism of action for both the genotoxicity and carcinogenicity induced by these PAHs (Cheung et al 1993;Fuchs et al 1993aFuchs et al , 1993bGlatt et al 1993;Lecoq et al 1989Lecoq et al , 1991aWood 1979). It is also of note that these three compounds, as well as benzo[a]pyrene, induced neoplastic cell transformation in at least one cell line (see Table 2-5).…”

Dibenzanthracenes and benzochrysenes elicit both genotoxic and nongenotoxic events in rat liver ‘stem-like’ cells

“…It has been documented, to a various extent, that benzochrysenes and dibenzanthracenes form DNA adducts and are mutagenic, with BgChry being the most potent genotoxin (Lecoq et al, 1989;Nesnow et al, 1994;Giles et al, 1995Giles et al, , 1996Giles et al, , 1997Lloyd and Hanawalt, 2002). In contrast to BgChry, DBahA, despite its known mutagenicity and carcinogenicity in vivo, has been shown to form relatively low levels of DNA adducts in vitro (Binková anď Srám, 2004;Staal et al, 2006).…”

“…However, data on their carcinogenicity are mostly available only for DBahA, which is classified as probable human carcinogen (IARC, 1983). The carcinogenic effects of these PAHs are mostly attributed to their ability to be metabolised to diol epoxides, with bay or fjord regions, forming DNA adducts in vitro (Lecoq et al, 1989;Lecoq et al, 1991;Giles et al, 1995Giles et al, , 1996Giles et al, , 1997. The dihydrodiol epoxides of BgChry and BcChry induce mammary tumours in female rats (Amin et al, 1995a(Amin et al, , 2003 and this metabolite of BgChry also induces high numbers of liver and lung tumours in newborn mice (Amin et al, 1995b).…”

Carbocations from dibenz[a,j]anthracene and dibenz[a,h]anthracene, their methylated derivatives, and oxidized metabolites: A stable ion and DFT study

“…15 As for DB[a,c]A, it is an active tumorigen that formed the 10,11-, 3,4-and the 1,2-dihydrodiols in metabolic studies. 16 Several studies have dealt with the synthesis of these dihydrodiols.…”

“…Whereas parent 1 and its carbocations are planar, methylation at C-7 induces slight deviations (up to 14 o ). The situation changes in the C-7/C-14 dimethyl-derivative 3 and its carbocations, where the structure becomes significantly more distorted out of planarity (for example 16 o angle between AC and CE rings in 3). The correspondence between the reported X-ray structure 20 and the computed gas phase structure seems poor ( Charts S2-S3 address the relative aromaticity in DBAs 1-4 and their carbocations by using NICS(1) zz .…”