Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic compounds are known carcinogens. Although many carcinogens are also mutagens, we have previously shown that sodium arsenite is not mutagenic at either the Na+/K+ ATPase or hprt locus in Chinese hamster V79 cells. It can, however, enhance UV-mutagenesis. We now confirm the nonmutagenicity of sodium arsenite in line G12, a pSV2gpt-transformed V79 (hprt-) cell line, which is able to detect multilocus deletions in addition to point mutations and small deletions. The lack of arsenic mutagenicity has led to studies emphasizing its comutagenicity. Sodium arsenite at relatively nontoxic concentrations (5 microM for 24 h or 10 microM for 3 h) is comutagenic with N-methyl-N-nitrosourea (MMU) at the hprt locus in V79 cells. Using a nick translation assay, which measures DNA strand breaks by incorporating radioactive deoxyribonucleoside monophosphate at their 3'OH ends in permeabilized cells, we found that much more incorporation was seen in cells treated with MNU (4 mM, 15 min) followed by 3-h incubation with 10 microM sodium arsenite compared with cells exposed to the same MNU treatment followed by 3-h incubation without sodium arsenite. This result shows that in the presence of arsenite, strand breaks resulting from MNU or its repair accumulate over a 3-h period. We suggest that the repair of MNU-induced DNA lesions may be inhibited by arsenite either by affecting the incorporation of dNMPs into the MNU-damaged DNA template or by interfering with the ligation step.
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PMID:Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea. 248 16

N-Methyl-N-nitrosourea (MNU) reacts with DNA to produce a variety of lesions, of which O6-methylguanine (O6-MeG) has been implicated in the mutagenic and carcinogenic effects of this agent. The present study aimed to investigate the types and position specificities of mutations induced by MNU. Mutational sequence alterations were determined for 53 independent mutations induced by MNU in a cDNA of the human hprt gene, which is stably integrated into chromosomes of the mouse cell line VH12. The majority of the mutations induced by MNU were base substitutions (85%), mostly GC to AT transitions (41/43), and the remainder (15%) were frameshift or deletion mutations resulting from loss or addition of a few bases. The transition mutations occurred preferentially at the middle G in 5'-purine-G-N-3' sequences in the non-transcribed strand, and were distributed nonrandomly over the coding region of the gene. Analysis of the results suggests that, when interpreting mutational specificity and distribution, not only the nature of the mutational target sequence, but also the functional domains of the protein should be considered.
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PMID:Specificity of mutations induced by N-methyl-N-nitrosourea in a cDNA of the hprt gene. 847 39

Comparison of results derived from transgenic animal gene-mutation assays with those from mutation analyses in endogenous genes is an important step in the validation of the former. We have used lambda lacZ transgenic mice to study alkylation-induced mutagenesis in vivo in (a) lacZ and hprt in spleen cells, and (b) lacZ and Dlb-I in small intestine from lambda lacZ+/0/Dlb-Ia/b mice. Induction of mutations by ethyl- and methylnitrosourea (ENU, MNU) and ethyl methanesulphonate (EMS) was investigated at 7 weeks after a single i.p. dose of each of these chemicals. In the small intestine, treatment with various dosages of ENU (10-150 mg/kg) resulted in a linear dose-response in both lacZ and Dlb-I. MNU (30 mg/kg) was also mutagenic in lacZ and Dlb-I, while EMS (250 mg/kg) did not significantly induce mutations in either gene. In spleen, ENU gave a linear dose-related response in both lacZ and hprt, MNU induced mutation sin both lacZ and hprt, and EMS was only positive for lacZ. No differences in response were observed between single and split-dose treatment with ENU (1 x 50 or 5 x 10 mg/kg with a 1- or 7-day interval), both in spleen and small intestine, except for lacZ in small intestine, where the single high dose gave a significantly higher induction than the split dose with the 7-day interval. The overall results suggest that mutagenic effects of fractionated doses are generally additive. In most cases, the induction factor (ratio treated over controls) for mutations in lacZ was lower than that for hprt and Dlb-I, presumably due to a higher background in lacZ and/or a lower mutability of lacZ. The general concordance between the data for lacZ and the endogenous genes indicates that lambda lacZ transgenic mice are a suitable model to study induction of gene mutations in vivo.
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PMID:Gene-mutation assays in lambda lacZ transgenic mice: comparison of lacZ with endogenous genes in splenocytes and small intestinal epithelium. 971 Dec 65