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

To investigate which specific kinds of base changes are induced by psoralen adducts in the genomic DNA of diploid human fibroblasts, cells were exposed to 8-methoxypsoralen (8-MOP) at 2-12 microM followed by one dose of UVA (365 nm) irradiation (PUVA-I treatment) or two doses of UVA (PUVA-II treatment). While PUVA-I treatment produced little effect on the induction of cytotoxicity, PUVA-II treatment significantly reduced the fibroblasts' colony-forming ability and resulted in about 10-fold increases in mutation frequency at the D0 dose. Mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of 36 independent PUVA-II mutants were characterized by direct sequencing of cDNA amplified by the polymerase chain reaction (PCR). Seventeen mutants contained single base substitutions and the other 19 mutants either lacked one or more exons, or had deleted or gained nucleotides in the exon boundaries in their cDNA. The intron--exon boundaries of 10 of these 19 putative splicing mutants were further characterized by direct sequencing of the PCR-amplified hprt gene. The results showed that nine contained single base substitutions at the consensus splicing donor and acceptor sites. One splicing mutant possessed two base substitutions located at exon 8, whereas its splicing sites were intact. Most of the base substitutions occurred at T-A base pairs (24/29). The majority of T.A changes occurred at thymine of 5'TA and 5'ATA on the non-transcribed strand. Four of the five G.C base substitutions were located at guanines of 5'TG sites adjacent 3' to AT or TA sequences. In addition, the occurrence of a specific type of mutation was highly correlated to the 5' flanking bases of TA sites. The mutagenesis of 13 of the 16 mutational events at 5'TA sites on the non-transcribed strand can be explained by the preferential incisions of the photoadducts on the transcribed strand followed by misalignment--realignment during translesion repair synthesis of the bulky lesions on the non-transcribed strand.
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PMID:Mutation specificity of 8-methoxypsoralen plus two doses of UVA irradiation in the hprt gene in diploid human fibroblasts. 831 9

Cadmium and lead have been shown to induce cellular transformations and gene mutations in cultured rodent cells, as well as tumours in live animals. However, the mechanisms by which these metals cause cellular transformations and mutations in human cells have not been explored. In this study, we investigated the abilities of cadmium and lead to induce anchorage-independent transformations and hprt gene mutations in diploid human fibroblasts. Human fibroblasts were exposed to either cadmium acetate (0-60 microM) or lead acetate (0-2 mM) for 24 h. After removal of the metals, the cells were kept in exponential growth for 7 and 9 days before mutation and anchorage-independence assays were taken, respectively. Both cadmium and lead significantly induced anchorage-independent colonies in dose-dependent manners; the frequencies of anchorage-independent colonies induced by these metals were similar to those induced by N-methyl-N'-nitro-N-nitrosoguanidine at approximately equal cytotoxic dose ranges (30-10% survival). 3-Aminotriazole at non-cytotoxic dosages decreased catalase activity by >80%, and markedly enhanced cadmium-induced cytotoxicity and anchorage-independent colonies. Cadmium uptake by human fibroblasts was not affected by 3-aminotriazole co-administered with 10 microM of cadmium; whereas cadmium uptake and accumulation were enhanced 1.5-fold by 3-aminotriazole co-administered with 1-2.5 microM of cadmium. Lead-induced anchorage-independence or cytotoxicity was not affected by 3-aminotriazole co-treatment; however, 3-aminotriazole did significantly enhance lead uptake and accumulation in human fibroblasts. Neither cadmium- nor lead-induced 6-thioguanine-resistant mutation frequency in human fibroblasts. Co-administering these metals with 3-aminotriazole did not enhance mutations in human fibroblasts. These results suggest that cadmium and lead may both act as tumour promoters in diploid human fibroblasts, and that reactive oxygen species is more important in cadmium- than lead-induced cytotoxicity and anchorage-independence.
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PMID:Effect of 3-aminotriazole on anchorage independence and mutagenicity in cadmium- and lead-treated diploid human fibroblasts. 963 78