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Gene Review

OTC  -  ornithine carbamoyltransferase

Homo sapiens

Synonyms: OTCase, Ornithine carbamoyltransferase, mitochondrial, Ornithine transcarbamylase
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Disease relevance of OTC


Psychiatry related information on OTC

  • OBJECTIVES: This study examined whether the change in nicotine replacement therapy sales from prescription to over the counter (OTC) status affected smoking cessation [5].
  • RESULTS: Initial symptoms of OTC deficiency were nonspecific and included feeding difficulties, lethargy, and "respiratory distress"; vomiting was infrequent [6].
  • OBJECTIVE:: This article compares the decision-making process of the FDA's Nonprescription Drugs Advisory Committee (NDAC) in 3 cases of a proposed switch from prescription to over-the-counter (OTC) status involving a nicotine replacement therapy product, 2 statins, and an emergency oral contraceptive [7].
  • Excessive alcohol consumption may further increase this risk and the FDA is requiring warnings on over-the-counter (OTC) NSAIDs [8].
  • The purpose of the present study was to describe associations between the use of common over-the-counter (OTC) and prescription medications with individual differences in salivary cortisol in infants and their mothers [9].

High impact information on OTC


Chemical compound and disease context of OTC

  • We did not observe a significant difference between the risk of toxicity with OTC naproxen versus OTC ibuprofen (adjusted OR, 0.84; 95% CI, 0.26-2.70) [14].
  • Recombinant adenoviruses deleted in E1 and containing a human OTC cDNA expressed little functional OTC enzyme in vivo and had no observable impact on the underlying metabolic abnormalities of the OTC-deficient mouse (i.e. elevated urinary orotate and serum glutamine) [15].
  • Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations [16].
  • Oxidative stress and glutathione (GSH) deficit may play an important role in HIV infection pathogenesis, and oral administration of GSH-replenishing drugs such as N-acetylcysteine (NAC) and 2-oxothiazolidine-4(R)-carboxylic acid (OTC) may be associated with an increased survival rate of HIV-infected patients [17].
  • In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles [18].

Biological context of OTC


Anatomical context of OTC

  • The cytoplasmically synthesized precursor of the mitochondrial matrix enzyme, ornithine transcarbamylase (OTC), is directed to mitochondria by its amino-terminal leader peptide [23].
  • Prenatal diagnosis by amniocentesis has not been feasible because OTC is not expressed in amniocytes and because no unusual metabolites can be detected in amniotic fluid [24].
  • The biological activity of the cloned OTC complementary DNA was tested by joining it with SV40 (an animal virus) regulatory elements and transfecting cultured HeLa cells, which do not normally express OTC [2].
  • We propose that these point mutations, which result in aberrant splicing of the OTC pre-mRNAs, lead to OTC deficiency through either decreased efficiency of mRNA export from the nucleus to the cytosol or synthesis of enzyme subunits that are unstable and rapidly degraded [25].
  • OTC activity in the necropsied liver tissue was reduced to approximately 12% of the control and that of COS 1 cells transfected with Arg40His OTC cDNA was 10.2 +/- 1.8% of the control transfected with wild type OTC cDNA [26].

Associations of OTC with chemical compounds

  • Furthermore, the growth of the OTC-deficient Hep3B tumor cells (ASS-positive and ADI-resistant) in mice was inhibited by treatment with rhArg-peg(5,000mw), which is active alone and is synergistic in combination with 5-fluorouracil [19].
  • There was full agreement between the results of mutational analysis and of allopurinol testing in the patients and their female relatives, supporting the value of the allopurinol test in the detection of carriers of OTC deficiency [22].
  • To restore the urea cycle, HepG2 cells were transfected with full length Ornithine Transcarbamylase and Arginase I cDNA constructs under a CMV promoter [1].
  • Radiolabelled enzyme assays showed that Ornithine Transcarbamylase functional activity was missing but that Carbamoyl Phosphate Synthase I, Arginosuccinate Synthetase and Arginosuccinate Lyase were functionally expressed at levels comparable to cultured primary human hepatocytes [1].
  • Gene expression data from HepG2 cells revealed that although expression of three urea cycle genes Carbamoyl Phosphate Synthase I, Arginosuccinate Synthetase and Arginosuccinate Lyase was evident, Ornithine Transcarbamylase and Arginase I expression were completely absent [1].
  • Biochemical characterizations revealed that OTC Lys88 acetylation decreases the affinity for carbamoyl phosphate, one of the two OTC substrates, and the maximum velocity, whereas the K(m) for ornithine, the other OTC substrate, is not affected [27].

Regulatory relationships of OTC


Other interactions of OTC

  • At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome [30].
  • The location of the RP3 locus was found to be 0.4 cM distal to OTC in the Xp21.1 region, and that of the RP2 locus was 6.5 cM proximal to DXS7 in Xp11.2-p11 [31].
  • The genetic distance was found to be approximately 10cM between 754 and DMD (two crossovers in 26 meioses) and to be approximately 10cM between OTC and DMD (two crossovers in 26 meioses) [32].
  • One locus (RP3) has been closely defined by genetic linkage and deletion analyses and localised to the region between the ornithine transcarbamylase (OTC) and chronic granulomatous disease (CYBB) loci in Xp21.1-p11 [33].
  • Pairwise linkage analysis maps the gene for CSNB1 at Xp11.3 and suggests that the CSNB1 locus is distal to another Xp11 marker, TIMP, and proximal to the OTC locus [34].

Analytical, diagnostic and therapeutic context of OTC

  • Electroporation and transient assay in Cos1 indicated that the specific activity of mutant OTC was 100-fold lower than that of wild type [35].
  • To characterize mutations responsible for OTC deficiency, we used the PCR to amplify cDNAs prepared from patient livers which demonstrated no OTC enzyme activity and no OTC cross-reacting material on western blots [25].
  • Northern blotting of liver RNA from these patients demonstrated (a) reduced, but significant, amounts of OTC mRNA in one of the patients who had a deleted exon 7 but (b) very little OTC mRNA in the other two patients [25].
  • In family B, the index case came to attention as OTC deficiency, after the transplantation of his liver when the recipient died of cerebral edema and hyperammonemia [36].
  • Restriction mapping and Southern blot analyses demonstrated that one of the clones covers the 5'-end region of the OTC gene [37].


  1. Ornithine transcarbamylase and arginase I deficiency are responsible for diminished urea cycle function in the human hepatoblastoma cell line HepG2. Mavri-Damelin, D., Eaton, S., Damelin, L.H., Rees, M., Hodgson, H.J., Selden, C. Int. J. Biochem. Cell Biol. (2007) [Pubmed]
  2. Structure and expression of a complementary DNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase. Horwich, A.L., Fenton, W.A., Williams, K.R., Kalousek, F., Kraus, J.P., Doolittle, R.F., Konigsberg, W., Rosenberg, L.E. Science (1984) [Pubmed]
  3. Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. Roepman, R., van Duijnhoven, G., Rosenberg, T., Pinckers, A.J., Bleeker-Wagemakers, L.M., Bergen, A.A., Post, J., Beck, A., Reinhardt, R., Ropers, H.H., Cremers, F.P., Berger, W. Hum. Mol. Genet. (1996) [Pubmed]
  4. Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene. Hentzen, D., Pelet, A., Feldman, D., Rabier, D., Berthelot, J., Munnich, A. Hum. Genet. (1991) [Pubmed]
  5. Effect on smoking cessation of switching nicotine replacement therapy to over-the-counter status. Thorndike, A.N., Biener, L., Rigotti, N.A. American journal of public health. (2002) [Pubmed]
  6. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. Maestri, N.E., Clissold, D., Brusilow, S.W. J. Pediatr. (1999) [Pubmed]
  7. The decision-making process of us food and drug administration advisory committees on switches from prescription to over-the-counter status: A comparative case study. Nguyen, N.T., Cook, D.M., Bero, L.A. Clinical therapeutics. (2006) [Pubmed]
  8. The effect of alcohol abuse on the risk of NSAID-related gastrointestinal events. Neutel, C.I., Appel, W.C. Annals of epidemiology. (2000) [Pubmed]
  9. Individual differences in salivary cortisol: associations with common over-the-counter and prescription medication status in infants and their mothers. Hibel, L.C., Granger, D.A., Kivlighan, K.T., Blair, C. Hormones and behavior. (2006) [Pubmed]
  10. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Meindl, A., Dry, K., Herrmann, K., Manson, F., Ciccodicola, A., Edgar, A., Carvalho, M.R., Achatz, H., Hellebrand, H., Lennon, A., Migliaccio, C., Porter, K., Zrenner, E., Bird, A., Jay, M., Lorenz, B., Wittwer, B., D'Urso, M., Meitinger, T., Wright, A. Nat. Genet. (1996) [Pubmed]
  11. Long-term treatment of girls with ornithine transcarbamylase deficiency. Maestri, N.E., Brusilow, S.W., Clissold, D.B., Bassett, S.S. N. Engl. J. Med. (1996) [Pubmed]
  12. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. Arn, P.H., Hauser, E.R., Thomas, G.H., Herman, G., Hess, D., Brusilow, S.W. N. Engl. J. Med. (1990) [Pubmed]
  13. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. Hauser, E.R., Finkelstein, J.E., Valle, D., Brusilow, S.W. N. Engl. J. Med. (1990) [Pubmed]
  14. Risk of serious upper gastrointestinal toxicity with over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs. Lewis, J.D., Kimmel, S.E., Localio, A.R., Metz, D.C., Farrar, J.T., Nessel, L., Brensinger, C., McGibney, K., Strom, B.L. Gastroenterology (2005) [Pubmed]
  15. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors. Ye, X., Robinson, M.B., Batshaw, M.L., Furth, E.E., Smith, I., Wilson, J.M. J. Biol. Chem. (1996) [Pubmed]
  16. The toxicology of hydroquinone--relevance to occupational and environmental exposure. DeCaprio, A.P. Crit. Rev. Toxicol. (1999) [Pubmed]
  17. Synthesis and in vitro anti-HIV activity in human monocyte-derived macrophages of 2-oxothiazolidine-4(R)-carboxylic acid derivatives. Oiry, J., Puy, J.Y., Mialocq, P., Clayette, P., Fretier, P., Jaccard, P., Dereuddre-Bosquet, N., Dormont, D., Imbach, J.L. J. Med. Chem. (1999) [Pubmed]
  18. Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo. Trifonova, R.T., Pasicznyk, J.M., Fichorova, R.N. Antimicrob. Agents Chemother. (2006) [Pubmed]
  19. Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion. Cheng, P.N., Lam, T.L., Lam, W.M., Tsui, S.M., Cheng, A.W., Lo, W.H., Leung, Y.C. Cancer Res. (2007) [Pubmed]
  20. Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells. Mart??nez-Jim??nez, C.P., G??mez-Lech??n, M.J., Castell, J.V., Jover, R. J. Biol. Chem. (2006) [Pubmed]
  21. Mental retardation locus in Xp21 chromosome microdeletion. Fries, M.H., Lebo, R.V., Schonberg, S.A., Golabi, M., Seltzer, W.K., Gitelman, S.E., Golbus, M.S. Am. J. Med. Genet. (1993) [Pubmed]
  22. Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency. Climent, C., García-Pérez, M.A., Sanjurjo, P., Ruiz-Sanz, J.I., Vilaseca, M.A., Pineda, M., Campistol, J., Rubio, V. Hum. Mutat. (1999) [Pubmed]
  23. Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide. Horwich, A.L., Kalousek, F., Fenton, W.A., Pollock, R.A., Rosenberg, L.E. Cell (1986) [Pubmed]
  24. Gene deletion and restriction fragment length polymorphisms at the human ornithine transcarbamylase locus. Rozen, R., Fox, J., Fenton, W.A., Horwich, A.L., Rosenberg, L.E. Nature (1985) [Pubmed]
  25. Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency. Carstens, R.P., Fenton, W.A., Rosenberg, L.R. Am. J. Hum. Genet. (1991) [Pubmed]
  26. Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult. Matsuda, I., Matsuura, T., Nishiyori, A., Komaki, S., Hoshide, R., Matsumoto, T., Funakoshi, M., Kiwaki, K., Endo, F., Hata, A., Shimadzu, M., Yoshino, M. J. Med. Genet. (1996) [Pubmed]
  27. Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals. Yu, W., Lin, Y., Yao, J., Huang, W., Lei, Q., Xiong, Y., Zhao, S., Guan, K.L. J. Biol. Chem. (2009) [Pubmed]
  28. Cholestatic Jaundice and IgA Nephropathy Induced by OTC Muscle Building Agent Superdrol. Jasiurkowski, B., Raj, J., Wisinger, D., Carlson, R., Zou, L., Nadir, A. Am. J. Gastroenterol. (2006) [Pubmed]
  29. An investigation of the factors affecting community pharmacists' selection of over the counter preparations. Kennedy, E., Moody, M. Pharmacy world & science : PWS. (2000) [Pubmed]
  30. Phenotype-genotype correlations in X linked retinitis pigmentosa. Kaplan, J., Pelet, A., Martin, C., Delrieu, O., Aymé, S., Bonneau, D., Briard, M.L., Hanauer, A., Larget-Piet, L., Lefrançois, P. J. Med. Genet. (1992) [Pubmed]
  31. Heterogeneity analysis in 40 X-linked retinitis pigmentosa families. Teague, P.W., Aldred, M.A., Jay, M., Dempster, M., Harrison, C., Carothers, A.D., Hardwick, L.J., Evans, H.J., Strain, L., Brock, D.J. Am. J. Hum. Genet. (1994) [Pubmed]
  32. Human X chromosome markers and Duchenne muscular dystrophy. Davies, K.E., Speer, A., Herrmann, F., Spiegler, A.W., McGlade, S., Hofker, M.H., Briand, P., Hanke, R., Schwartz, M., Steinbicker, V. Nucleic Acids Res. (1985) [Pubmed]
  33. Genetic localisation of the RP2 type of X linked retinitis pigmentosa in a large kindred. Wright, A.F., Bhattacharya, S.S., Aldred, M.A., Jay, M., Carothers, A.D., Thomas, N.S., Bird, A.C., Jay, B., Evans, H.J. J. Med. Genet. (1991) [Pubmed]
  34. Assignment of the gene for complete X-linked congenital stationary night blindness (CSNB1) to Xp11.3. Musarella, M.A., Weleber, R.G., Murphey, W.H., Young, R.S., Anson-Cartwright, L., Mets, M., Kraft, S.P., Polemeno, R., Litt, M., Worton, R.G. Genomics (1989) [Pubmed]
  35. An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells. Lee, J.T., Nussbaum, R.L. J. Clin. Invest. (1989) [Pubmed]
  36. Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon. Ploechl, E., Ploechl, W., Stoeckler-Ipsiroglu, S., Pokorny, H., Wermuth, B. Clin. Genet. (2001) [Pubmed]
  37. Isolation and characterization of the human ornithine transcarbamylase gene: structure of the 5'-end region. Hata, A., Tsuzuki, T., Shimada, K., Takiguchi, M., Mori, M., Matsuda, I. J. Biochem. (1986) [Pubmed]
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