Aldo-Keto Reductases (AKRs) are a superfamily of monomeric 37kDa NAD(P)(H) dependent oxidoreductases that act as reductases in vivo to convert ketones and aldehydes to secondary and primary alcohols, respectively for subsequent conjugation reactions. In humans 15 AKRs exist and details on their kinetic and catalytic mechanism and structural biology exist. AKR1D1 is the only human steroid 5β-reductase and reduces double bonds while AKR1C members exhibit nitroreductase activity expanding the AKR substrate repertoire. Our work has focused on the AKR1C subfamily and their roles in the metabolic activation of aryl hydrocarbons using LC/MS. Aryl hydrocarbons are suspect human carcinogens that pollute the environment represented by the pyrogenic polycyclic aromatic hydrocarbons (PAH; e.g. benzo[a]pyrene); the alkylated and oxygenated petrogenic PAH that come from oil-spills (e.g. C1-C4 phenanthrenes and C1-C2 chrysenes); and the nitro-PAH that come from diesel exhaust. AKR1C enzymes compete with the formation of diol-epoxides by converting PAH-trans-dihydrodiols to electrophilc and redox-active o-quinones; these are delivered by the aryl hydrocarbon receptor to the nucleus, generate 8-oxo-dGuo which mutates the p53 tumor suppressor gene to impact lung cancer initiation. Less is known about the metabolic activation of alkylated-PAH, and some cannot form diol-epoxides due to alkylation. Common metabolites formed include bis-electrophiles that may act as cross-linking agents as well as catechol-conjugates that can be used as urinary biomarkers for risk assessment of oil exposure in humans. Nitro-PAH can be reduced by AKR1C subfamily members to the corresponding hydroxylamino-derivatives for activation by sulfonation. The human AKR1C genes are among the most highly induced by the Nrf2-Keap1 system by the electrophiles and reactive-oxygen species that they generate suggesting that a functional consequence of AKR upregulation is enhanced aryl hydrocarbon activation. These findings suggest that the chemopreventive roles of Nrf2 activators is context dependent [Supported by P30-ES013508 to TMP].

Human aldo-keto reductases and aryl hydrocarbon activation

254th National Meeting (2017)

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