Influence of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan.

In the present study, we have investigated the role of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan. Hepatic microsomes were used to investigate the aerobic metabolism of naphtho[2,1-b]furan (compound A), 2-nitro-naphtho[2,1-b]furan (compound B) and 7-methoxy-naphtho [2,1-b]furan (compound C) and comparison of the metabolites formed was made using HPCL analysis and NMR, mass and UV-visible spectrometry. The different metabolic pathways investigated were compared with the previously reported metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (compound D). Naphtho[2,1-b]furan yield metabolites of both the furan and benzene rings, while metabolites formed from 7-methoxy-naphtho[2,1-b]furan and 2-nitro-naphtho [2,1-b]furan were derived entirely as a result of enzymic attack on the first benzene ring.

Microsomal metabolism of dibenz[a,c]anthracene, dibenz[a,h]anthracene and dibenz[a,j]anthracene to bis-dihydrodiols and polyhydroxylated products.

Polar, ethyl acetate soluble metabolites formed in incubations of dibenz[a,c]anthracene (DB[a,c]A), dibenz[a,h]anthracene (DB[a,h]A) and the related DB[a,h]A 3,4-diol and dibenz[a,j]anthracene (DB[a,j]A) with 3-methylcholanthrene (3-MC)-induced rat liver microsomal preparations have been separated by HPLC and examined using fluorescence, UV and NMR spectroscopy. Metabolites with spectral properties consistant with their identification as the 3,4:8,9-bis-diol of DB[a,j]A and a 1,2,3,4,12,13-hexol derived from DB[a,c]A were found. DB[a,h]A was metabolized to three polar products identified as the 3,4:10,11-bis-diol and the related 1,2,3,4,8,9- and 1,2,3,4,10,11-hexols, which were also formed, together with the related 1,2,3,4-tetrol, from the DB[a,h]A 3,4-diol. The possible role of bis-diols in the metabolic activation of these three dibenzanthracenes is discussed.

Reactivity with DNA of three pyrenofuran analogues of benzo(a)pyrene and benzo(e)pyrene.

Three pyrenofurans, the pyreno[1,2-b]furan (FP1), the pyreno[2,1-b] furan (FP2) and the pyreno[4,5-b]furan (FP3) have been synthesized as analogues of the mutagenic and carcinogenic benzo(a)pyrene (FP1 and FP2) and of its non-carcinogenic isomer benzo(e)pyrene (FP3). For each of the pyrenofurans, the reactivity with DNA has been tested in presence of liver microsomes of rats induced with 3-methylcholanthrene. Fluorescence spectroscopy showed that only FP2 and FP3 which possess a "bay region" react with DNA. In both cases, metabolites bound to DNA have a fluorescence emission comparable to that of the "bay region" dihydrodiols obtained after the "in vitro" metabolism of initial molecules. FP2 is shown to react similarly to benzo(a)pyrene whereas the reactivity of FP3 is different from that of benzo(e)pyrene, in spite of their structural similarities. This is probably due to reasons of three-dimensional space configuration. The peculiar reactivity of FP3 is predicted by calculations of the bond order values.

Oxidative metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) by the microsomal system isolated from 3-methylcholanthrene-induced rat liver.

The metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan and the subsequent binding to DNA, under aerobic conditions, were investigated using liver microsomes of both untreated rats and rats pre-treated with 3-methylcholanthrene [3-MC]. The metabolites were analyzed by HPLC. The following compounds: 7-hydroxy-2-nitro-naphtho[2,1-b]-furan-6,9-dione; 6,7-dihydro-2-nitro-naphtho[2,1-b]furan; 7-hydroxy-2-nitro-naphtho[2,1-b]furan and 6-hydroxy-7-methoxy-2-nitro-naphtho[2,1-b]furan have been identified by their UV-visible, mass spectra, NMR spectra and by comparison to an authentic reference sample. Qualitative and quantitative metabolic charts involving only ring oxidation have been established.

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

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.

Free radical production during photo-assisted NADPH reduction of four alpha-nitroarenofurans.

Generation of radical anions during NADPH reduction of four mutagenic and genotoxic alpha-nitroarenofurans was examined. ESR showed that free radicals were generated during reduction solely in the presence of light. Computer simulations of ESR spectra were in good agreement with the experimental ones.