Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

7H-dibenzo[c,g]carbazole (DBC) is a potent liver and skin carcinogen when topically applied to the back skin of mice. This compound is found in complex mixtures produced during incomplete combustion of fossil fuels as well as in wood and tobacco smoke. The objective of this study was to elucidate the mechanism of action of this compound by assessing the Ha-ras mutational spectra of skin and liver tumors induced in a mouse model system. Low doses (50 nmol) and high doses (100 nmol) of DBC were applied topically to the backs of Hsd:ICR(Br) mice twice weekly. No treatment and solvent application were used as controls. After the mice were killed, the skin and liver tumors were removed, DNA was isolated, and tumor DNA was screened for Ha-ras codon 12, 13, and 61 mutations by using an enriched polymerase chain reaction method. Mutations were confirmed by reverse cyclic dideoxy sequencing. No mutations were found in codons 12 and 13 of DBC-induced tumors, whereas one acetone-control tumor had a codon 13 mutation. Sixty-seven percent of skin tumors and 45% of liver tumors induced by high doses of DBC and 67% of skin tumors induced by low doses of DBC contained codon 61 mutations, whereas liver tumors induced by low doses of DBC did not. The codon 61 mutations were exclusively A:T-->T:A transversions within the second base (CAA-->CTA). These results indicate that DBC is a unique polycyclic aromatic hydrocarbon in that it induces both skin and liver tumors upon topical application and that the mutational spectra are the same in tumors from two target organs, skin and liver, yet different from tumors from a third target organ, lung.
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PMID:Frequent Ha-ras mutations in murine skin and liver tumors induced by 7H-dibenzo[c,g]carbazole. 1036 12

Carcinogenic N-heterocyclic aromatic hydrocarbons are formed during the incomplete combustion of fossil fuels as well as cigarette smoke. N-Methyldibenzo[c,g]carbazole (NMeDBC) and 7H-dibenzo[c,g]carbazole (DBC) are members of this group. DBC induces mouse skin and liver tumors, whereas NMeDBC induces only mouse skin tumors. The objective of this study was to elucidate the mechanism of action of these compounds in skin by assessing the Ha-ras mutational spectra induced by a two-stage initiation-promotion protocol. NMeDBC (200 nmol) or DBC (200 nmol) was applied to the back skin of 24 female Hsd:ICR(Br) mice (12 per group) once. 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 microg) was then applied twice weekly for 28 wk. Tumors were screened for Ha-ras mutations using enriched polymerase chain reaction and mutations defined by dideoxy sequencing. In DBC animals 58% produced papillomas, of which 71% had codon 61 mutations, 4% had codon 12 mutations, 4% had codon 13 mutations, and 21% had no Ha-ras mutations. In NMeDBC animals 92% produced papillomas, of which 73% had codon 61 mutations and 27% had no Ha-ras mutations. All of the codon 61 mutations, from both NMeDBC and DBC, were CAA-->CTA transversions. The DBC-induced tumors with the codon 12 mutation had a GGA-->GAA transition, and the codon 13 mutation was a GGC-->GTC transversion. These results suggest that NMeDBC is a more potent tumor inducer than DBC, but the resulting H-ras mutations in each group were predominantly in codon 61, and, therefore, mutation induction in skin by each chemical appears to proceed by a similar mechanism.
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PMID:Comparison of Ha-ras mutational spectra of N-methyldibenzo[c,g]carbazole and 7H-dibenzo[c,g]carbazole-induced mouse skin tumors. 1174 17