Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycyclic aromatic hydrocarbons: a comprehensive review

Abstract

The Unified Theory of PAH Carcinogenicity accommodates the activities of methylated and non-methylated polycyclic aromatic hydrocarbons (PAHs) and states that substitution of methyl groups on meso-methyl substituted PAHs with hydroxy, acetoxy, chloride, bromide or sulfuric acid ester groups imparts potent cancer producing properties. It incorporates specific predictions from past researchers on the mechanism of carcinogenesis by methyl-substituted hydrocarbons, including (1) requirement for metabolism to an ArCH2X type structure where X is a good leaving group and (2) biological substitution of a meso-methyl group at the most reactive center in non-methylated hydrocarbons. The Theory incorporates strong inferences of Fieser: (1) The mechanism of carcinogenesis involves a specific metabolic substitution of a hydrocarbon at its most reactive center and (2) Metabolic elimination of a carcinogen is a detoxifying process competitive with that of carcinogenesis and occurring by a different mechanism. According to this outlook, chemical or biochemical substitution of a methyl group at the reactive meso-position of non-methylated hydrocarbons is the first step in the mechanism of carcinogenesis for most, if not all, PAHs and the most potent metabolites of PAHs are to be found among the meso methyl-substituted hydrocarbons. Some PAHs and their known or potential metabolites and closely related compounds have been tested in rats for production of sarcomas at the site of subcutaneous injection and the results strongly support the specific predictions of the Unified Theory.

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

“…It can also be found in car exhausts and is present in cigarette smoke condensate at higher concentrations than the reference PAH, benzo [a] pyrene (BaP) (Bakhiya et al 2006). Alkylated PAHs like 1-MP require metabolic activation into electrophilic intermediates to exert their genotoxic effects (Flesher and Lehner 2016). Alkylated PAHs like 1-MP require metabolic activation into electrophilic intermediates to exert their genotoxic effects (Flesher and Lehner 2016).…”

“…Like unsubstituted polycyclic aromatic hydrocarbons (PAHs), alkylated PAHs are also formed through incomplete combustion of organic matter, although preferentially at lower combustion temperatures (Flesher and Lehner 2016). They can also be generated as a result of diagenic processes of organic sediments (e.g., mineral oil and coal) (Richter-Brockmann and Achten 2018).…”

“…1-MP is hepatocarcinogenic in rodents (Rice et al 1987) but to date insufficient data are available on the carcinogenic risk to humans. Alkylated PAHs like 1-MP require metabolic activation into electrophilic intermediates to exert their genotoxic effects (Flesher and Lehner 2016). CYP-catalyzed biotransformation of 1-MP yields 1-hydroxymethylpyrene (1-HMP), which is further activated by sulfotransferases (SULTs), particularly SULT1A1, to 1-sulfoxymethylpyrene (1-SMP) ( Fig.…”

Cosmetics use and age at menopause: is there a connection?

“…Surprisingly, the study also found that chronic low dose exposure to the three PAHs was more toxic compared to acute high dose exposure (81). PAHs have also been found to be anti-androgenic, estrogenic, carcinogenic, and potentially genotoxic (79, 82–84). …”

Selective Killing of Cancer Cells by Nonplanar Aromatic Hydrocarbon‐Induced DNA Damage

“…[2] actually show carcinogenic effects, while PAHs usually would not induce tumors directly. [11] Besides, based on the similar property of binding to DNA, some PAHs such as substituted anthracene [12] and pyrene ring systems have exhibited an anticancer efficiency and been also used clinically to treat several leukemias and some solid tumors. [12a,13] Therefore, the biological functions of PAHs derivatives as carcinogens or anticancer agents might highly depend on their molecular skeletons and substitutions.…”