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)

The antioxidant butylated hydroxyanisole (BHA) and the promutagen/carcinogen 7,12-dimethylbenz[a] anthracene (DMBA) were examined for mutagenicity and the induction of sister chromatid exchanges (SCE) in a hepatocyte-mediated mutation assay with V79 Chinese hamster lung cells. Rat and hamster hepatocytes, prepared by in situ collagenase perfusion, were compared in the mutation assay to determine whether there are species differences in the ability to activate BHA and DMBA to ultimate mutagens. At the marginally cytotoxic concentration of 1.0 microM (2.6 micrograms/ml), DMBA induced a significant increase in the frequency of SCE and in the number of mutations to 6-thioguanine resistance (6-TGR) at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus with either rat or hamster hepatocyte-mediated activation, but induced highest mutation frequencies with rat hepatocytes. These findings support the contention that species differences can affect mutational response in hepatocyte-mediated assays with V79 cells. BHA was strongly cytotoxic to V79 cells at dose levels in excess of 0.3 mM (54 micrograms/ml). In contrast to DMBA, BHA showed no evidence of genotoxicity at marginally cytotoxic concentrations up to and including 0.3 mM as shown by the inability of this antioxidant to increase the frequency of sister chromatid exchanges or to induce mutations to 6-thioguanine resistance when activation was provided by rat or hamster hepatocytes.
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PMID:Lack of induction of sister chromatid exchanges and of mutation to 6-thioguanine resistance in V79 cells by butylated hydroxyanisole with and without activation by rat or hamster hepatocytes. 392 92

Matrix metalloproteinases (MMPs) comprise a family of more than 20 members, each with the ability to degrade components of the extracellular matrix. The interstitial collagenases have the unique capacity to degrade the stromal collagens, types I, II and III, the body's most abundant proteins. These collagenases include MMP-1, MMP-8, MMP-13 and MMP-14. MMP-1, with a very broad expression pattern, has major roles in mediating matrix destruction in many diseases. We have described a single nucleotide polymorphism (SNP) in the MMP-1 promoter that augments transcription. This SNP is the presence or absence of an extra guanine (G) at -1607 bp, which creates the sequence 5'-GGAA-3'(2G allele), and which is an ETS binding site. Compared to the 1G allele (5'-GAA-3'), the 2G SNP is associated with enhanced transcription of MMP-1 and increased enzymatic activity. Although murine systems are often used to model human diseases, mice have only distant homologues of human MMP-1. Therefore, we used a technique for the targeted insertion of a single copy of a gene at the HPRT locus to compare expression of the 1G and 2G alleles. We generated transgenic mice with -4372 bp of the human MMP-1 promoter containing either the 1G or 2G SNP in front of the lac Z (E.coli ss-galactosidase) gene. We measured the relative expression of the transgenes in vitro in embryonic stem (ES) cells and in fibroblasts derived from embryonic mice. Our data show modest constitutive expression of ss-galactosidase mRNA and protein from these alleles, with the 2G allele more transcriptionally active than the 1G allele. We conclude that these mice represent a model for integration of a single copy of the human MMP-1 promoter into the murine genome, and could be used to study MMP-1 gene expression in a murine system.
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PMID:Site controlled transgenic mice validating increased expression from human matrix metalloproteinase (MMP-1) promoter due to a naturally occurring SNP. 1957 45