Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.
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PMID:In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N-nitrosopyrrolidine, 2-amino-3-methylimidazo[4,5-f]quinoline, and di(2-ethylhexyl)phthalate. 1548 47

Di-(2-ethylhexyl) phthalate (DEHP), the common plasticizer used in the production of polyvinyl chloride, can be converted to the more potent metabolite mono-ethylhexyl phthalate (MEHP). Epidemiological studies have shown an association with elevated induction of rat hepatic cancer and reproductive toxicity in response to MEHP exposure. However, the mechanism of genotoxicity and carcinogenicity induced by MEHP treatment remains unclear. As a means to elucidate the mechanisms of action, lethality and mutagenicity in the adenine phosphoribosyltransferase (aprt+/-) gene induced in several CHO cell types by MEHP were assessed. Dose-response relationships were determined in the parental AA8 cell line, its nucleotide repair-deficient UV5 and base repair-deficient EM9 subclones, and also in AS52 cells harboring the bacterial guanine-hypoxanthine phosphoribosyltransferase (gpt) gene and its derived AS52-XPD-knockdown and AS52-PARP-1-knockdown cells. Treatment of AS52 with MEHP led to intracellular production of reactive oxygen species (ROS) and DNA strand breaks in a dose-dependent manner. Separately, mutations in the gpt gene of AS52 cells were characterized and found to be dominated by G:C to A:T and A:T to G:C transitions. Independent AS52-mutant cell (ASMC) clones were collected for the sequential in vivo xenograft tumorigenic studies, 4 of total 20 clones had aggressive tumor growth. Moreover, microarray analysis indicated miR-let-7a and miR-125b downregulated in ASMC, which might raise oncogenic MYC and RAS level and activate ErbB pathway. Comparative evaluation of the results indicates that the principal mechanism of this mutagenic action is probably to be through generation of ROS, causing base excision damage resulting in carcinogenicity.
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PMID:Acute exposure to DEHP metabolite, MEHP cause genotoxicity, mutagenesis and carcinogenicity in mammalian Chinese hamster ovary cells. 2842 79