Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Steroids. 2014 Jan;79:49-63. doi: 10.1016/j.steroids.2013.10.012. Epub 2013 Nov 1.

Abstract

Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ(4)-3-ketosteroid-5β-reductase (steroid 5β-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.

Keywords: 17β-hydroxysteroid dehydrogenase type 6; 3α/β-Diol; 5α-androstane-3α/β,17β-diol; 5α-reductase type 1 or 2; 5α/β-DHT; 5α/β-dihydrotestosterone; AKR; AR; Bile-acids; CAR; COMT; CRPC; CYP; Cancer; DSD; ER; FXR; G protein coupled bile acid receptor; GABA; GPBAR1; HSD17B6; Hydroxysteroid dehydrogenase; Inherited mutations; MAF; N-methyl-d-aspartate; NMDA; Neurosteroids; PR; PXR; SDR; SND; SNP; SRD5A1/A2; SULT; Synthetic steroids; UDP glucuronosyl transferase; UGT; aldo–keto reductase; androgen receptor; castrate resistant prostate cancer; catechol-O-methyl transferase; constitutive androstane receptor; cytochrome P450 superfamily; disordered sexual dysgenesis; estrogen receptor; farnesoid X receptor; minor allelic frequency; pregnane X receptor; progesterone receptor; short-chain dehydrogenase/reductase; single nucleotide difference; single nucleotide polymorphism; sulfotransferase; γ-aminobutyric acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / genetics
  • 20-Hydroxysteroid Dehydrogenases / metabolism*
  • Bile Acids and Salts / deficiency
  • Disorders of Sex Development / enzymology
  • Disorders of Sex Development / genetics
  • Humans
  • Mutation
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Steroids / metabolism*

Substances

  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • Steroids
  • Oxidoreductases
  • 20-Hydroxysteroid Dehydrogenases
  • 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
  • trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
  • 3-oxo-5 beta-steroid delta 4-dehydrogenase