Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolites of two structurally related chemical carcinogens, benzo[a]pyrene and 1-nitropyrene, were compared for their ability to cause cytotoxicity and induce mutations in normally repairing or nucleotide excision repair-deficient diploid human fibroblasts; for their ability to induce mutations in a defined gene sequence, supF, when a plasmid containing adducts formed by these carcinogens replicates in human 293 cells; and for their ability to induce homologous recombination between duplicated genes in mouse L cells. Both of the metabolites tested, i.e., (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha, epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and 1-nitrosopyrene (1-NOP), form adducts on guanine. BPDE binds principally at the N2 position of guanine; 1-NOP binds to guanine at the C8 position. Results of the studies in diploid human cells indicated that when compared on the basis of equal numbers of DNA adducts, BPDE is more effective than 1-NOP in inducing mutations in DNA repair-proficient cells, but when compared in repair-deficient xeroderma pigmentosum human cells that do not remove such adducts from their DNA, the frequency of mutants induced per adduct is equal. These results suggest that during the time available for repair of potentially mutagenic lesions, repair-proficient human cells excise 1-NOP adducts more rapidly than they excise BPDE adducts. Molecular analysis of the specific kinds of mutations induced when a plasmid containing BPDE residues was allowed to replicate in human cells showed that BPDE induces mainly base substitution mutations, predominantly G:C to T:A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutations and homologous recombination induced in mammalian cells by metabolites of benzo[a]pyrene and 1-nitropyrene. 312 87

Nitro derivatives of polycyclic aromatic hydrocarbons are produced primarily as the result of incomplete combustion. Nitropyrenes have been identified as primary mutagenic compounds of diesel emission particulate and are tumorigenic in laboratory animals. Since nitropyrenes do not react directly with DNA, their effects presumably are mediated through cellular conversion of the parent compounds into reactive species. For example, 1-nitropyrene (1-NP) is activated by enzymatic reduction to 1-nitrosopyrene (1-NOP), followed by reduction to the hydroxylamine, which undergoes decomposition to yield a nitrenium ion, that reacts with DNA. The cytotoxic effects of 1-nitropyrene and 1-nitrosopyrene were compared in fibroblasts from normal persons, from excision-repair-deficient xeroderma pigmentosum (XP) patients, and from a patient with an inherited predisposition to malignant melanoma of the skin (hereditary cutaneous malignant melanoma [HCMM]). HCMM cells are more sensitive than normal cells to the cytotoxic and mutagenic effects of 4-nitroquinoline-1-oxide, and they form more DNA adducts per concentration of this agent than do normal cells. However, the HCMM cells exhibit the same sensitivity as normal cells to 4-hydroxyaminoquinoline-1-oxide, which suggests they are more capable than normal cells of metabolizing the parent compound into a more reactive form. On the basis of concentration, 1-NOP was much more cytotoxic than 1-NP. With both compounds, the normal cells exhibited a shoulder on their survival curves that was lacking for the XP cells. The dose of 1-NP giving 37% survival was 46 microM for a series of four normal cell lines, 22 microM for the HCMM cell line tested, and 12 microM for the XP cell line. The slope of the 1-nitropyrene survival curve for XP cells was 2.5 times steeper than the slope of the curve of the normal cells; the slope of the 1-NP survival curve for the HCMM cells was intermediate between the XP cells and the normal fibroblasts. The slope of the 1-nitrosopyrene survival curve for XP cells was also 2.5 times steeper than that for the normal cells, but the HCMM cells showed a normal response. If the resistance of normal cells to the cytotoxic effect of these compounds reflects their ability to remove potentially cytotoxic adducts from their DNA before these lesions cause cell death, normal cells should require a higher initial number of DNA adducts than XP cells do to cause a particular degree of cell killing.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on the metabolism and biological effects of nitropyrene and related nitro-polycyclic aromatic compounds in diploid human fibroblasts. 326 56

The cytotoxic and mutagenic effects of 1-nitropyrene (1-NP) and its reduced metabolite 1-nitrosopyrene (1-NOP) were determined in diploid human fibroblasts. Conditions for the metabolic activation of the parent compound (1-NP) by human cells in culture were developed. The cytotoxic effect of 1-NP in normal cells was compared with that for repair-deficient xeroderma pigmentosum (XP) cells, and cells from a patient with hereditary cutaneous malignant melanoma (HCMM), which we have shown earlier are abnormally sensitive to 4-nitroquinoline-1-oxide. The slope of the survival curve for XP cells was 2.5 times steeper than that of normal cells; that of HCMM cells was intermediate. When these cells were exposed to 1-NOP, the slope of the survival curve for the XP cells was also 2.5 times steeper than normal but the HCMM cells showed a normal response, suggesting that their defect is not in repair of DNA adducts, but in activation. 1-NP and 1-NOP also proved to be mutagenic in the human cell assay. When compared on the basis of concentration, 1-NOP was much more mutagenic than 1-NP. But when the compounds were compared on the basis of equal cell killing or equal number of DNA adducts initially bound to DNA, they were very similar. An equal number of residues covalently bound to DNA caused approximately the same amount of cell killing for either compound. XP cells were killed by a 7-fold lower number of bound adducts, suggesting that the increased survival and decreased mutation induction in the normal cells reflects their ability to remove potentially cytotoxic and mutagenic lesions.
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PMID:Cytotoxic and mutagenic effects of 1-nitropyrene and 1-nitrosopyrene in diploid human fibroblasts. 394 46