Tissue Distribution, Ontogeny, and Chemical Induction of Aldo-Keto Reductase Genes in Mice
Matthew Pratt-Hyatt, Andrew J. Lickteig, and Curtis D. Klaassen
Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, Kansas 66160
Aldo-keto reductases (Akrs) are a conserved group of NAD(P)(H)-dependent oxido-reductase enzymes. There are fifteen Akr families, which are classified by protein sequence homology. Mammalian Akrs are found in the Akr1, Akr6, and Akr7 families. This study provides a comprehensive examination of the tissue distribution for the 16 substrate metabolizing Akrs in mice, their expression during development and whether they are increased by xenobiotic-induced transcriptional pathways. Akr1c6, 1c14, 1c20, and 1c22 are primarily present in liver; Akr1a4, 1c18, 1c21, and 7a5 in kidney; Akr1d1 in liver and kidney; Akr1b7 in small intestine; Akr1b3 and Akr1e1 in brain; Akr1b8 in testes; Akr1c14 is in ovaries; whereas Akrs1c12, 1c13, and 1c19 are expressed in numerous tissues. Many of the Akr1c genes as well as Akr1d1 are lowly expressed before birth and during early post-natal development. The expression of Akr genes do not mature until after the onset of early adulthood in mice. In addition, CAR, PXR, and Nrf2 transcription factors assist in the regulation of Akrs. CAR activation leads to increased mRNA expression of Akr1c6, Akr1c19, and Akr1d1; whereas PXR activation causes a repression of Akr1c13 and Akr1c20 mRNA. The Nrf2 inducer CDDO-Im, as well as data from Nrf2-null or Nrf2 over-expressing mice, demonstrates that Nrf2 activation causes an increase in Akr1c6 and Akr1c19 mRNA expression. In conclusion, the present study examined the ontogeny of Akrs mRNA in mouse liver and demonstrated that similar to drug metabolizing enzymes and transporters, the mRNA of Akr1c6, 1c14, 1c19, 1c20 and 1d1 increases after birth and continues to increase to adulthood. This study also demonstrates that CAR, PXR, and Nrf2 transcriptional pathways influence the transcription of Akr genes.