Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Abstract

Aldo-keto reductases (AKRs) are a superfamily of NAD(P)H linked oxidoreductases that are generally monomeric 34-37kDa proteins present in all phyla. The superfamily consists of 15 families, which contains 151 members (www.med.upenn.edu/akr). Thirteen human AKRs exist that use endogenous substrates (sugar and lipid aldehydes, prostaglandins, retinals and steroid hormones), and in many instances they regulate nuclear receptor signaling. Exogenous substrates include metabolites implicated in chemical carcinogenesis: NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), polycyclic aromatic hydrocarbon trans-dihydrodiols, and aflatoxin dialdehyde. Promoter analysis of the human genes identifies common elements involved in their regulation which include osmotic response elements, anti-oxidant response elements, xenobiotic response elements, AP-1 sites and steroid response elements. The human AKRs are highly polymorphic, and in some instances single nucleotide polymorphisms (SNPs) of high penetrance exist. This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis.

Fig. 1

AKR Isoforms and the Metabolism of Lipid Aldehydes

Fig. 2

AKR1C3 as Prostaglandin F Synthase

Fig. 3

AKR1B10 as a Retinal Reductase

Fig. 4

Role of Human AKRs in PAH-Activation

Fig. 5

Role of Human AKRs in NNK Metabolism

Fig. 6

Role of Human AKRs in Aflatoxin Metabolism

Fig. 7

TESS transcription factor consensus sequence search through the promoter regions of human AKR genes. Promoters (-9000 to −1.0 kb; ATG +1) of the human genes indicated were searched for matches to the following consensus sequences: AP-1 (blue; TGACTCA); ARE (red; (G)TGA(G/C)NNNGC); XRE (green; TNGCGTG); Steroid Response Element −1 (0.5 site; yellow GGTACA); ERE (gray; GGTgANNNTGACC, cGTCANNNTGACC, GGTCANNNtGACC) and ORE (black;, consensus TGGAAAATAT, TGGAAAAATTT, TGGAAAATCA (consensus sequences with a change of only one nucleotide at positions in italics are noted on the figure)). ARE = antioxidant response element, XRE = xenobiotic response element, ERE = estrogen response element, and ORE = osmotic response element.