Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using an O-acetyltransferase-overexpressing strain Salmonella typhimurium NM2009 we measured the activities for metabolic activation of several carcinogenic arylamines to genotoxic products by rat liver microsomal cytochrome P-450 enzymes, and compared them with the activities obtained in the original tester strain Salmonella typhimurium TA1535/pSK1002 or the O-acetyltransferase-defective strain Salmonella typhimurium NM2000. Since all of the tester strains had introduced the umuC'-'lacZ gene, we could detect the genotoxic activities by measuring bacterial beta-galactosidase activity resulting from the DNA damage. In the O-acetyltransferase-defective strain NM2000 most of the arylamines tested showed weak responses in inducing umu gene expression after metabolic activation by liver microsomes. The strain NM2009, on the other hand, was found to be highly sensitive towards a variety of aromatic amines, and these activities were greater than those seen in the original tester strain S. typhimurium TA1535/pSK1002. The chemicals which marked responses in strain NM2009 include 2-aminoanthracene, 6-aminochrysene, 2-aminofluorene, 2-acetylaminofluorene, 3-methoxy-4-aminoazobenzene, O-aminoazotoluene, Glu-P-1, Trp-P-2, A alpha C, MeA alpha C, MeIQ, MeIQx and IQ. Of these procarcinogens tested MeIQ, MeIQx and IQ also showed strong cytotoxic effects in S. typhimurium NM2009 after metabolic activation by liver microsomes. Only PhIP was the substrate showing similar responses in strains TA1535/pSK1002 and NM2009. The results with the reconstituted monooxygenase system containing purified cytochrome P-450 enzymes support the above findings obtained with the liver microsomal enzyme system. Thus, the usefulness of the newly developed strain NM2009 for the detection of reactive metabolites of several carcinogenic aromatic amines after metabolism by the liver microsomal cytochrome P-450-linked monooxygenase system has been ascertained.
 ...
PMID:Use of a newly developed tester strain Salmonella typhimurium NM2009 for the study of metabolic activation of carcinogenic aromatic amines by rat liver microsomal cytochrome P-450 enzymes. 138 50

A highly sensitive umu test system for the detection of carcinogenic/mutagenic aromatic amines has been developed utilizing a new tester strain, Salmonella typhimurium NM2009, possessing an elevated O-acetyltransferase (O-AT) level. NM2009 was constructed by subcloning the bacterial O-AT gene into a plasmid vector pACYC184 and introducing the plasmid into the original strain S. typhimurium TA1535/pSK1002 harboring an umuC'-'lacZ fusion gene. The system is based on the ability of DNA-damaging agents (genotoxins) to induce umuC gene expression and monitored by measuring the cellular beta-galactosidase activity evoked by the fusion gene. Twenty-two aromatic amine compounds including arylamines, aminoazo dyes, and heterocyclic aromatic amines were tested for inducibility of DNA damage after metabolic activation by rat liver S9 in strain NM2009 and the sensitivity was compared with those of the parent strain TA1535/pSK1002 and the O-AT-defective strain NM2000. NM2009 had about 400 times higher O-AT activity than the parent strain. It was found that NM2009 was much more sensitive to aromatic amines than other strains to induce umuC gene expression after metabolic activation; the chemicals which were extremely sensitive in strain NM2009 include 2-aminoanthracene, 2-aminofluorene, 2-acetylaminofluorene, benzidine, 6-aminochrysene, 2,4-diaminotoluene, 2,6-diaminotoluene, 1-naphthylamine, o-tolidine, 3-MeO-AAB, o-aminoazotoluene, Glu-P-1, Trp-P-1, MeA alpha C, A alpha C, MeIQ, MeIQx, and IQ. In contrast, Trp-P-2 and PhIP showed almost similar sensitivities in three tester strains used in this study. These results suggest that strain NM2009 with high O-acetyltransferase activity is very useful to detect the genotoxic activities of potential mutagenic aromatic amine compounds, which require metabolic activation via the cytochrome P-450/acetyltransferase system.
 ...
PMID:Development of high sensitive umu test system: rapid detection of genotoxicity of promutagenic aromatic amines by Salmonella typhimurium strain NM2009 possessing high O-acetyltransferase activity. 788 66

The importance of environmental and dietary arylamines, and heterocyclic amines in the etiology of human cancer is of growing interest. These pre-carcinogens are known to undergo bioactivation by cytochrome P450 (CYP)-directed oxidation, which then become substrates for the UDP-glucuronosyltransferases (UGTs). Thus, glucuronidation may contribute to the elimination of CYP-mediated reactive intermediate metabolites, preventing a toxic event. In this study, human UGTs were analyzed for their ability to modulate the mutagenic actions of N-hydroxy-arylamines formed by CYP1A2. Studies with recombinant human UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7 and UGT2B15 expressed in heterologous cell culture confirmed that UGT1A9 glucuronidated the mutagenic arylamines N-hydroxy-2-acetylaminofluorene (N-hydroxy-2AAF) and 2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine (N-hydroxy-PhIP). To examine the mutagenic potential of these agents, a genotoxicity assay was employed using Salmonella typhimurium NM2009, a bacterial strain expressing the umuC SOS response gene fused to a beta-galactosidase reporter lacZ gene. DNA modification results in the induction of the umuC gene and subsequent enhancement of beta-galactosidase activity. Both N-hydroxy-2AAF and N-hydroxy-PhIP stimulated a dose-dependent increase in bacterial beta-galactosidase activity. In addition, the procarcinogens 2AAF and PhIP were efficiently bioactivated to bacterial mutagens when incubated with Escherichia coli membranes expressing CYP1A2 and NADPH reductase. CYP1A2 generated 2AAF- and PhIP-mediated DNA damage, but only the action of N-hydroxy-2AAF was blocked by expressed UGT1A9. These results indicate that UGT1A9 can control the outcome of a genotoxic response. The results also indicate that while a potential toxicant such as N-hydroxy-PhIP can serve as substrate for glucuronidation, its biological actions can exceed the capacity of the detoxification pathway to prevent the mutagenic episode.
 ...
PMID:The contribution of UDP-glucuronosyltransferase 1A9 on CYP1A2-mediated genotoxicity by aromatic and heterocyclic amines. 1137 3