Disease relevance of OTC

• Ornithine transcarbamylase and arginase I deficiency are responsible for diminished urea cycle function in the human hepatoblastoma cell line HepG2 [1].
• The sequence of mature human OTC resembles that of the subunits of both OTC and aspartate transcarbamylase from Escherichia coli [2].
• The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11 [3].
• Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of the urea cycle in humans and is responsible for lethal neonatal hyperammonemia in males [4].
• Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes [4].

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

• The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping [10].
• BACKGROUND: Ornithine transcarbamylase is an X-linked mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine [11].
• Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma [12].
• Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes [13].
• Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women [13].

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

• Therefore, pretreatment tumor gene expression profiling of ASS and OTC could aid in predicting tumor response to arginine depletion with arginine-depleting enzymes [19].
• Transfection of HCC cells with OTC resulted in resistance to rhArg [19].
• Finally, insulin treatment of human hepatocytes and HepG2 cells caused repression of PGC1alpha and a concomitant down-regulation of ApoCIII, PEPCK, AldoB, and OTC [20].
• In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers [21].
• Another four female patients were heterozygous for point mutations in the OTC gene: the nonsense mutation Q69X or the missense mutations I172F, G188V and G197R [22].

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

• Cholestatic Jaundice and IgA Nephropathy Induced by OTC Muscle Building Agent Superdrol [28].
• A postal survey of pharmacists in a random sample of community pharmacies in Great Britain was carried out to ascertain the factors which influenced their decisions when recommending a product for Over The Counter (OTC) sale [29].

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].

References