The Role of Human Aldo-Keto Reductases in the Metabolic Activation and Detoxication of Polycyclic Aromatic Hydrocarbons: Interconversion of PAH Catechols and PAH o-Quinones

Abstract

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants. They are procarcinogens requiring metabolic activation to elicit their deleterious effects. Aldo-keto reductases (AKR) catalyze the oxidation of proximate carcinogenic PAH trans-dihydrodiols to yield electrophilic and redox-active PAH o-quinones. AKRs are also found to be capable of reducing PAH o-quinones to form PAH catechols. The interconversion of o-quinones and catechols results in the redox-cycling of PAH o-quinones to give rise to the generation of reactive oxygen species and subsequent oxidative DNA damage. On the other hand, PAH catechols can be intercepted through phase II metabolism by which PAH o-quinones could be detoxified and eliminated. The aim of the present review is to summarize the role of human AKRs in the metabolic activation/detoxication of PAH and the relevance of phase II conjugation reactions to human lung carcinogenesis.

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

“…S1D; refs. 20,21). This was confirmed by qRT-PCR for Nqo1, aldo-keto reductase (Akr)1b8, carbonyl reductases (Cbr)1 and Cbr3, and for Gsta2, Gsta3 and Gstm1 in the epidermis of untreated and 1Â DMBA-treated mice ( Fig.…”

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

“…CYP1A1 is essential to convert 1-NP into metabolites with much less toxicity (Su et al, 2011), and consequently, it decreases 1-NP's genotoxicity and cell death threat. In contrast, BaP is metabolized into genotoxic intermediates by CYP1A1 (Zhang et al, 2012).…”

“…B[a]P-7,8-diol may be further converted to B[a]P diol epoxide (BPDE). BDBP has been shown to bind to DNA and is regarded as a carcinogenic derivative (Badal and Delgoda, 2014;Zhang et al, 2012). BDBP may also interact with other cellular components, resulting in cell death or damage.…”

“…However, in phase I, some reactive intermediates may interact with DNA and other cellular components, resulting in toxic effects. Both groups of enzymes, cytochrome p450 (CYP) and aldoketo reductases (AKRs), can be referred to as phase I drug-metabolizing enzymes (Zhang et al, 2012).…”

Editorial on research topic: aldo-keto reductases and role in human disease

“…The article by Ruiz et al (2012) describes the retinaldehyde reductase activity of AKRs in relation to proliferation and tumorigenesis. The paper from the Penning group (Zhang et al, 2012) summarizes the role of AKR in the metabolic activation and detoxication of polycyclic aromatic hydrocarbons and the relevance of phase II conjugation reactions to human lung carcinogenesis. Rižner (2012) provides a review on the role played by AKR1B and AKR1C members in the pathogenesis of endometrial and cervical cancers, as well as other uterine diseases.…”