Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutagenic heterocyclic amines are metabolized to mutagens which act directly on Salmonella typhimurium by P-448 forms of cytochrome P-450. These direct mutagens are N-hydroxylated heterocyclic amines, such as N-hydroxy-Trp-P-1, N-hydroxy-Trp-P-2, N-hydroxy-Glu-P-1, N-hydroxy-Glu-P-2, N-hydroxy-IQ, N-hydroxy-2-amino-alpha-carboline (N-hydroxy-A alpha C), and N-hydroxy-2-amino-3-methyl-alpha-carboline (N-hydroxy-MeA alpha C). The treatment of rats with polychlorinated biphenyl stimulated N-hydroxylation of heterocyclic amines about 10- to 260-fold depending on the substrates used. The N-hydroxylation activities of purified cytochrome P-448-H and P-448-L were markedly different. P-448-H, which had very low activity for benzo[a] pyrene metabolic activation, showed high N-hydroxylation activity. The activity ratio P-448-H:P-448-L was markedly different depending on the amines used. This ratio was 45, 22, 3, and 0.02, respectively, for Glu-P-1, IQ, Trp-P-2, and benzo[a] pyrene. On the other hand, N-acetylation of the heterocyclic amines was very low. Although marked species differences in the N-acetylation were observed, the activities of the heterocyclic amines were about 1/100 of that of 2-aminofluorene. N-Hydroxy-Trp-P-2 could react directly to DNA, but N-hydroxy-Glu-P-1 could not. Therefore we need to consider the presence of a further activating system in mammalian and bacterial cells. We observed that N-hydroxy-Trp-P-2 was activated by prolyl-t-RNA synthetase, but N-hydroxy-Glu-P-1 was not activated by the same system. In the bacterial cells, both N-hydroxy-Trp-P-2 and N-hydroxy-Glu-P-1 were not activated by prolyl-t-RNA synthetase. However, both hydroxylamines were activated by the acetyl-CoA-dependent mechanism in mammalian and bacterial cells. These results indicated that the O-acetylation is an important pathway for DNA damage by heterocyclic amines in chemical carcinogenesis.
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PMID:Metabolic activation of mutagenic heterocyclic aromatic amines from protein pyrolysates. 351 87

Mitogen-regulated protein/proliferin (mrp/plf) gene family transcripts rise in abundance as a response to diverse chemical and physical agents that promote morphological transformation in the murine C3H/10T1/2 cultured cell model of multi-step carcinogenesis. To determine if proliferin genes respond to tumor promoters in vivo, RNA was extracted from the whole skin of SENCAR mice after single applications of 2 or 20 microg 12-O-tetradecanoylphorbol-13-acetate (TPA); 3.2 or 32 nmole), 20 or 40 mg benzoyl peroxide (BPO; 83, 165 micromole), or acetone vehicle alone (2.72 mmole). RNA samples were prepared from treated skin areas, 2-48 h after painting. Mrp/plf-mRNA was not detected in Northern blot hybridizations, but large increases in mRNAs for ornithine decarboxylase gene and mRNA (odc), v-jun oncogene-related transcription factor gene and mRNA (junB), egr1 (early growth response protein gene and mRNA) were measured relative to beta 2 microglobulin gene and mRNA (b2m) mRNA in response to TPA. BPO induced small relative changes in these mRNAs. Reverse transcriptase (RT)-polymerase chain reactions (PCR) detected fully-processed MRP/plf-mRNA 16-48 h after TPA treatments in five of six animals, and in three of six BPO-treated animals. The MRP/plf-mRNA species expressed in the skin were predominantly plf1 and mrp3 as determined by gene-specific restriction enzyme sites within the RT-PCR products. Expression was either undetectable or found at low levels in acetone-painted controls and was not detected during the anagen phase of the normal hair growth cycle in unpainted animals. These results demonstrate that mrp/plf-mRNA is differentially expressed in murine skin in response to mechanistically distinct tumor promoters and has potential utility as a short-term biomarker for tumor promoting effects in chemical carcinogenesis.
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PMID:Mitogen-regulated protein/proliferin mRNA induction following single applications of tumor promoters to murine skin. 1592 Jul 18