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Gene Review

ALDH3A1  -  aldehyde dehydrogenase 3 family, member A1

Homo sapiens

Synonyms: ALDH3, ALDHIII, Aldehyde dehydrogenase 3, Aldehyde dehydrogenase family 3 member A1, Aldehyde dehydrogenase, dimeric NADP-preferring
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Disease relevance of ALDH3A1

  • Furthermore, 3H-HNE metabolism and HNE-induced toxicity were not affected in ALDH3A1-specific SiRNA- or antisense RNA-treated rat lenses, HLECs, or ALDH3A1-null mouse lenses [1].
  • RESULTS: Primary breast tumor ALDH1A1 and ALDH3A1 levels were highly predictive of their respective levels in paired metastatic breast tumors present in axillary lymph nodes (r2 = 0.80 and 0.85, respectively) [2].
  • Three different stable human breast adenocarcinoma sublines that overexpress ALDH3A1 and certain other enzymes, apparently as a consequence of constitutively upregulated gene transcription mediated by transactivated EpREs (electrophile responsive elements) present in the 5'-upstream regions of these genes [3].
  • To investigate in detail the biochemical properties and distribution of this protein in the human cornea, we expressed human ALDH3A1 in Sf9 insect cells using a baculovirus vector and raised monoclonal antibodies against ALDH3A1 [4].
  • We found that human lung tumor (A549) cells, which express high levels of ALDH3A1 protein, were significantly less susceptible to the antiproliferative effects of 4-hydroxynonenal compared to human hepatoma HepG2 or SK-HEP-1 cells that lack ALDH3A1 expression [5].

High impact information on ALDH3A1

  • In conclusion, these results suggest that ALDH3A1 may protect corneal epithelial cells against oxidative damage not only through its metabolic function but also by prolonging the cell cycle [6].
  • Immunohistochemistry and biochemical fractionation revealed that ALDH3A1 is localized both in the nucleus and cytosol of ALDH3A1-transfected cells, implying a possible association between the nuclear localization of the enzyme and its proliferation-suppressive functions [6].
  • We noticed a reduction in ALDH3A1 gene expression in actively proliferating primary human corneal epithelium explant cultures, indicating that ALDH3A1 expression is inversely correlated with replication [6].
  • Aldehyde dehydrogenase 3A1 (ALDH3A1) is a NAD(P)+-dependent enzyme that is highly expressed in mammalian corneal epithelial cells and has been shown to protect against UV- and 4-hydroxynonenal-induced cellular damage, mainly by metabolizing toxic lipid peroxidation aldehydes [6].
  • Here we report a novel function of ALDH3A1 as a negative cell cycle regulator [6].

Chemical compound and disease context of ALDH3A1


Biological context of ALDH3A1

  • We conclude that expression of the crystallin ALDH3A1 is decreased in repair phenotype human keratocytes, compared to normal human keratocytes [12].
  • Oxidation of the aldehyde moiety of HNE to a carboxyl by ALDH3A1 expressed in stably transfected cell lines drastically reduced its potency for growth inhibition and apoptosis induction [7].
  • Expression of ALDH3A1 by stable transfection in V79 cells conferred a high level of protection against growth inhibition by the medium-chain length aldehyde substrates with highest substrate activity, including hexanal, trans-2-hexenal, trans-2-octenal, trans-2-nonenal, and 4-hydroxy-2-nonenal (HNE) [7].
  • Duplication in the ALDH 3/10/7/8 gene cluster occurred in Phanerozoic period (about 300 million years ago) [13].
  • Rather, they are thought to up-regulate ALDH3A1 transcription via transient transactivation of an electrophile responsive element (EpRE) that is putatively also present in the 5'-upstream region of this gene [14].

Anatomical context of ALDH3A1

  • ALDH3A1 enzyme activity was not detectable in corneal fibroblasts (n=6) but was readily detected in corneal epithelial cells (0.29+/-0.1U/mg protein, n=4) and keratocytes (0.05+/-0.009U/mg protein, n=7) [12].
  • Compared to normal keratocytes, corneal fibroblast expression of ALDH3A1 mRNA was reduced by 27% (n=5) [12].
  • ALDH enzyme activity was also quantitated and immunolabeling was performed to determine the expression of ALDH3A1 in human corneal tissue sections from normal and diseased corneas [12].
  • We have developed transgenic cell lines to examine the potential for either human ALDH1A1 or ALDH3A1 to protect against damage mediated by these toxic aldehydes [7].
  • These observations were further expanded and confirmed on human keratinocyte cells (NCTC-2544) overexpressing ALDH3A1 [6].

Associations of ALDH3A1 with chemical compounds


Regulatory relationships of ALDH3A1

  • GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity [16].
  • Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5'-flanking regions [10].

Other interactions of ALDH3A1

  • METHODS: The metabolism of 3H-HNE was studied in ALDH3A1-knockout mouse lens and in HLECs transfected with ALDH1A1- or -3A1-specific antisense RNA and short interfering (Si)RNA [1].
  • Overexpression of human ALDH2, human ALDH3, and mouse Aldh-pb did not stimulate retinoic acid production [17].
  • Electrophile-initiated/EpRE-mediated induction of increased ALDH3A1 levels was found to be ER-independent [14].
  • Constitutive ALDH3A1 levels, as well as those of certain other drug-metabolizing enzymes, e.g. NQO1 and CYP1A1, are relatively low in cultured, relatively oxazaphosphorine-sensitive, human breast adenocarcinoma MCF-7 cells [3].
  • Still further, the three sublines may facilitate study of the signaling pathway that leads to transactivation of the EpREs present in the 5'-upstream regions of ALDH3A1, NQO1 and other gene loci [3].

Analytical, diagnostic and therapeutic context of ALDH3A1

  • ALDH3A1 protein expression as detected by western blotting was markedly reduced in passage zero fibroblasts and undetectable in higher passages (n=3) [12].
  • Recombinant ALDH3A1 protein was purified to homogeneity with a single-step affinity chromatography method using 5'-AMP-Sepharose 4B [4].
  • ALDH3 isozyme was isolated from a liver via carboxymethyl-Sephadex and blue Sepharose chromatographies and its kinetic constants for various substrates and coenzymes were determined [18].
  • Treatment with the DNA-damaging agents led to GSH depletion in control groups, although the depletion was significantly less in ALDH3A1-expressing cells [19].
  • Southern blot analysis of total genomic DNA argues against the proposed two-gene model for the ALDH3 isozymes (Yin, S.-J., Cheng, T.-C., Chang, C.-P., Chen, Y.-J., Chao, Y.-C., Tang, H.-S., Chang, T.-M., and Wu, C.-W. (1988) Biochem. Genet. 26, 343-360) [20].


  1. Role of aldehyde dehydrogenase isozymes in the defense of rat lens and human lens epithelial cells against oxidative stress. Choudhary, S., Xiao, T., Vergara, L.A., Srivastava, S., Nees, D., Piatigorsky, J., Ansari, N.H. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  2. Primary breast tumor levels of suspected molecular determinants of cellular sensitivity to cyclophosphamide, ifosfamide, and certain other anticancer agents as predictors of paired metastatic tumor levels of these determinants. Rational individualization of cancer chemotherapeutic regimens. Sreerama, L., Sládek, N.E. Cancer Chemother. Pharmacol. (2001) [Pubmed]
  3. Three different stable human breast adenocarcinoma sublines that overexpress ALDH3A1 and certain other enzymes, apparently as a consequence of constitutively upregulated gene transcription mediated by transactivated EpREs (electrophile responsive elements) present in the 5'-upstream regions of these genes. Sreerama, L., Sládek, N.E. Chem. Biol. Interact. (2001) [Pubmed]
  4. Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical characterization and immunohistochemical localization in the cornea. Pappa, A., Estey, T., Manzer, R., Brown, D., Vasiliou, V. Biochem. J. (2003) [Pubmed]
  5. Arachidonic acid suppresses growth of human lung tumor A549 cells through down-regulation of ALDH3A1 expression. Muzio, G., Trombetta, A., Maggiora, M., Martinasso, G., Vasiliou, V., Lassen, N., Canuto, R.A. Free Radic. Biol. Med. (2006) [Pubmed]
  6. Human aldehyde dehydrogenase 3A1 inhibits proliferation and promotes survival of human corneal epithelial cells. Pappa, A., Brown, D., Koutalos, Y., DeGregori, J., White, C., Vasiliou, V. J. Biol. Chem. (2005) [Pubmed]
  7. Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Townsend, A.J., Leone-Kabler, S., Haynes, R.L., Wu, Y., Szweda, L., Bunting, K.D. Chem. Biol. Interact. (2001) [Pubmed]
  8. Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Sládek, N.E., Kollander, R., Sreerama, L., Kiang, D.T. Cancer Chemother. Pharmacol. (2002) [Pubmed]
  9. Cellular levels of class 1 and class 3 aldehyde dehydrogenases and certain other drug-metabolizing enzymes in human breast malignancies. Sreerama, L., Sladek, N.E. Clin. Cancer Res. (1997) [Pubmed]
  10. Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and oxazaphosphorine-specific resistance. Sreerama, L., Rekha, G.K., Sladek, N.E. Biochem. Pharmacol. (1995) [Pubmed]
  11. Over-expression of glutathione S-transferases, DT-diaphorase and an apparently tumour-specific cytosolic class-3 aldehyde dehydrogenase by Warthin tumours and mucoepidermoid carcinomas of the human parotid gland. Sreerama, L., Sladek, N.E. Arch. Oral Biol. (1996) [Pubmed]
  12. Aldehyde dehydrogenase (ALDH) 3A1 expression by the human keratocyte and its repair phenotypes. Pei, Y., Reins, R.Y., McDermott, A.M. Exp. Eye Res. (2006) [Pubmed]
  13. Human aldehyde dehydrogenase gene family. Yoshida, A., Rzhetsky, A., Hsu, L.C., Chang, C. Eur. J. Biochem. (1998) [Pubmed]
  14. Transient induction of increased aldehyde dehydrogenase 3A1 levels in cultured human breast (adeno)carcinoma cell lines via 5'-upstream xenobiotic, and electrophile, responsive elements is, respectively, estrogen receptor-dependent and -independent. Sládek, N.E. Chem. Biol. Interact. (2003) [Pubmed]
  15. Aldehyde dehydrogenase-mediated cellular relative insensitivity to the oxazaphosphorines. Sládek, N.E. Curr. Pharm. Des. (1999) [Pubmed]
  16. Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases. Murphy, T.C., Arntzen, R., Picklo, M.J. Cardiovasc. Toxicol. (2005) [Pubmed]
  17. Genetic dissection of retinoid dehydrogenases. Duester, G. Chem. Biol. Interact. (2001) [Pubmed]
  18. Kinetic evidence for human liver and stomach aldehyde dehydrogenase-3 representing an unique class of isozymes. Yin, S.J., Liao, C.S., Wang, S.L., Chen, Y.J., Wu, C.W. Biochem. Genet. (1989) [Pubmed]
  19. Antioxidant function of corneal ALDH3A1 in cultured stromal fibroblasts. Lassen, N., Pappa, A., Black, W.J., Jester, J.V., Day, B.J., Min, E., Vasiliou, V. Free Radic. Biol. Med. (2006) [Pubmed]
  20. Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in Escherichia coli. Hsu, L.C., Chang, W.C., Shibuya, A., Yoshida, A. J. Biol. Chem. (1992) [Pubmed]
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