Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0451641 (urolithiasis)
 3,973 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular bases for hereditary cancer-prone diseases. 129 55

Terephthalic acid (TPA), dimethyl terephthalate (DMT), and melamine (MA) induced calculi and transitional cell hyperplasia in urinary bladders of rats. A high incidence of calculi was induced in weanling rats, but the incidence was much lower in adult rats ingesting the same dietary concentration of the chemical. The dose-response curves for the induction of urolithiasis in weanling rats were extremely steep, consistent with the fact that the formation calculi can occur in urine that is supersaturated, but not in urine that is undersaturated with respect to the stone components. In the cases of TPA and DMT, stones were composed primarily of calcium terephthalate (CaTPA). By determining the solubility of CaTPA, the concentration of TPA that would be required to achieve urinary saturation was calculated, and a conservative estimate of the amount of TPA or DMT that would have to be absorbed in order to induce calculi was derived. TPA and MA induced bladder tumors in rats in chronic feeding studies. However, it is likely that these tumors were secondary to the development of calculi. TPA and MA are apparently nongenotoxic, and they do not appear to be metabolized. Increased cell replication in the urothelium of the bladder caused by chronic physical injury was probably a major factor in the mechanism of induction of bladder tumors by bladder stones. Bladder neoplasms occurred primarily in the high dose groups, and they were usually, although not invariably, associated with stones. The possibility that stones were passed or were lost during processing of tissues for histopathologic examination could explain the absence of calculi from some of the neoplastic bladders. The formation of bladder calculi is an example of a threshold effect. Although there is strong evidence linking bladder stones with the induction of tumors, the existence of thresholds in chemical carcinogenesis continues to be controversial. A decision by the U.S. Environmental Protection Agency concerning the levels of MA allowed to occur in the food chain indicates that data regarding thresholds, even in the case of urolithiasis, are not being utilized in the risk assessment process.
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PMID:The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment. 390 81

The pharmacokinetics of [14C]terephthalic acid ([14C]TPA) were determined in Fischer-344 rats after intravenous and oral administration. After iv injection, the plasma concentration-time data were fitted using a three-compartment pharmacokinetic model. The average terminal half-life in three rats was 1.2 +/- 0.4 hr, and the average volume of distribution in the terminal phase was 1.3 +/- 0.3 liters/kg. Following administration by gavage, a longer terminal half-life was obtained, indicating that dissolution of [14C]TPA or absorption from the gut may be partially rate-limiting. Recovery of [14C]TPA in the urine following a bolus iv dose was 101 +/- 8%, indicating essentially complete urinary excretion of the compound. No evidence of metabolism of [14C]TPA was obtained by analysis of urine by high-performance liquid chromatography. [14C]TPA was transported to the fetus after administration of the compound to pregnant rats; however, the concentrations in fetal tissues were low relative to the corresponding maternal tissues. Neonatal rats exposed to 5% TPA in the diet of their dams did not develop calculi until the onset of self-feeding. These results demonstrate that TPA is rapidly excreted into urine after administration to rats, and that excretory mechanisms in the dam provide an effective mechanism of defense against TPA-induced urolithiasis in neonatal rats.
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PMID:Chemical urolithiasis. III. Pharmacokinetics and transplacental transport of terephthalic acid in Fischer-344 rats. 612 97

Exposure of male weanling Fischer 344 rats to 4.0% terephthalic acid (TPA) in the diet (positive controls) for two weeks (postnatal days 28-42) resulted in a 50% incidence of bladder calculi, aciduria, elevated urinary excretion of calcium (Ca) and magnesium (Mg), and slightly elevated serum levels of Ca and Mg relative to negative controls. Possible mechanisms of TPA-induced urolithiasis were examined by daily oral administration of allopurinol, chlorothiazide, or neutral phosphates, at their recommended therapeutic doses during exposure to dietary 4.0% TPA. An additional group was fed 4.0% TPA and 4.0% sodium bicarbonate in the diet for two weeks. Chlorothiazide or dietary bicarbonate abolished TPA-induced urolithiasis, but allopurinol and neutral phosphates had no effect. Bicarbonate increased water intake above that of positive controls and ameliorated the TPA-induced aciduria. It also increased urinary Mg and TPA above positive control values. Chlorothiazide reduced urinary Ca and TPA levels below those of positive controls. Treatment with chlorothiazide, neutral phosphates or bicarbonate slightly reduced serum Ca below the levels in either positive or negative controls. Drug treatment did not alter TPA-induced elevated serum Mg levels, but bicarbonate reduced serum Mg levels to negative control values. In conclusion, TPA-induced urolithiasis in male weanling rats was abolished by therapeutic agents which reduced urinary Ca and TPA excretion (chlorothiazide), or which enhanced water intake, urinary Mg and TPA excretion, and ameliorated TPA-induced aciduria (dietary bicarbonate). These factors appear to be critical for TPA-induced urolithiasis.
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PMID:Effects of selected therapeutic agents on urolithiasis induced by terephthalic acid in the male weanling Fischer 344 rat. 666 96