Relationship between GST Yp induction and hepatocyte proliferation in rats treated with phase II drug metabolizing enzyme inducers. (57/170)


Dynein light chain LC8 negatively regulates NF-kappaB through the redox-dependent interaction with IkappaBalpha. (58/170)


Hepatic glutathione S-transferases in mice fed on a diet containing the anticarcinogenic antioxidant butylated hydroxyanisole. Isolation of mouse glutathione S-transferase heterodimers by gradient elution of the glutathione-Sepharose affinity matrix. (59/170)

Induction of glutathione S-transferases (GSTs) is believed to represent an important mechanism whereby butylated hydroxyanisole inhibits chemical carcinogenesis. The soluble hepatic GSTs expressed by mice fed on normal diets are all homodimers comprising Ya3 (Mr 25,800), Yb1 (Mr 26,400) and Yf (Mr 24,800) subunits. In addition to these constitutively expressed GSTs, we have identified enzymes containing Ya1 (Mr 25,600), Ya2 (Mr 25,600), Yb2 (Mr 26,200) and Yb5 (Mr 26,500) subunits from the livers of Balb/c mice fed on diets containing butylated hydroxyanisole (BHA). Gradient affinity elution of GSH-Sepharose has been used to resolve the mouse liver enzymes into several discrete pools of activity from which GSTs were purified by cation-exchange chromatography. The inducible Mu-class Yb2 and Yb5 subunits were separately isolated as the heterodimers GST Yb1Yb2 and GST Yb1Yb5 and their catalytic properties are described; this showed that 1,2-dichloro-4-nitrobenzene and trans-4-phenylbut-3-en-2-one are marker substrates for the mouse Yb1 and Yb2 subunits respectively, but no discriminating model substrate was found that allows the identification of the Yb5 subunit. Individual GST subunits were resolved by reverse-phase h.p.l.c. and their amino acid compositions were determined. Certain subunits (Yb1, Yb2, Yb5 and Yf) were also subjected to automated amino acid sequence analysis, and this demonstrated that the Yb5 subunit has a blocked N-terminus. The mouse Yb1, Yb2 and Yb5 subunits from the major inducible Mu-class heterodimers were cleaved with CNBr and purified peptides from the Yb2 and Yb5 subunits were sequenced. These data show that the Yb2 subunit is distinct from the GSTs that are encoded by the cDNAs that have been cloned from mouse liver cDNA libraries but possesses identity with the protein that is encoded by pmGT2, a cDNA isolated from a mouse fibroblast cell line by Townsend, Goldsmith, Pickett & Cowan [(1989) J. Biol. Chem. 264. 21582-21590]. The sequence data also show that the cDNA encoding the mouse Yb5 subunit has not, to date, been cloned, and the relationship between this subunit and Mu-class GSTs in other species that possess a blocked N-terminus (e.g. rat GST YoYo) is discussed.  (+info)

Comparative study of the alkyl and peroxy radical-scavenging activity of 2-t-butyl-4-methoxyphenol (BHA) and its dimer, and their theoretical parameters. (60/170)

BACKGROUND: 2-t-Butyl-4-methoxyphenol (BHA) has considerable toxicity and undesirable potential tumor-promoting activities. To clarify the free radical mechanism of BHA-induced toxicity, the comparative radical-scavenging activity of BHA and its dimer (bis-BHA, 3,3'-ditert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol) with or without 2-mercapto-1-methylimidazole (MMI) was studied using the induction period method. MATERIALS AND METHODS: The induction period and propagation rate (Rp) were determined by differential scanning calorimetry (DSC) monitoring of polymerization of methyl methacrylate, initiated by the thermal decomposition of benzoyl peroxide (a source of the peroxy radical, PhCOO*) or 2,2'-azobisisobutyronitrile (a source of the alkyl radical, R*) under nearly anaerobic conditions. The anti-1,1'-diphenyl-2-picrylhydrazyl (DPPH) radical- and O2(-)-scavenging activities were also investigated. Furthermore, theoretical parameters were calculated from the DEFT/B3LYP and HF/6-31G*//B3LYP levels. RESULTS: For both PhCOO* and R* the inhibition rate constant (k(inh)) for BHA and bis-BHA was almost identical, but a marked decrease in the Rp(inh)/Rp(con) was found for the former. The BHA/MMI mixture (1:1 molar ratio) oxidized by R* reduced the total radical-scavenging activity by approximately 20% . BHA showed lower anti-DPPH radical- and higher O2(-)-scavenging activity. CONCLUSION: Upon PhCOO* or R* scavenging, BHA with a lower BDE, IP(koopman's), electronegativity, and electrophilicity value, but not bis-BHA with higher corresponding values, highly suppressed propagation. This may be due to the formation of highly reactive free-radical intermediates, which are potentially toxic.  (+info)

Alteration of aflatoxin B1 metabolic profiles and reduction of aflatoxin B1 mutagenicity by hepatic microsomes of rats fed butylated hydroxyanisole. (61/170)

Effect of administering butylated hydroxyanisole (BHA) on the metabolism of aflatoxin B1 (AFB1) and production of mutagenic metabolites have been compared with those of phenobarbital (PB) and 3-methylcholanthrene (MC) administration in rat liver microsomes. Male Sprague-Dawley rats were treated with these inducers and liver microsomes were isolated. These microsomes were used to metabolize AFB1 and to produce mutagenic metabolites. Results showed that normal rat liver were able to metabolize AFB1 quite actively and produced large amounts of AFB-8,9-epoxide (appearing as the AFB-8,9-dihydrodiol-Tris complex). Upon incubations of normal rat liver microsomes with increasing concentrations of AFB1, a steep dose-related increases of mutagenicity was observed in the Ames test. The PB-microsomes had an increased ability to metabolize AFB1 and particularly the rate for the production of the weakly mutagenic AFQ1 metabolite was markedly increased. Conversely, PB-microsomes had a moderate decrease in its ability to form the strongly mutagenic of AFB-8,9-epoxide metabolite. However, the ability of PB-microsomes to form mutagenic metabolites from AFB1 was somewhat greater than that of the control-microsomes. The MC-microsomes had an increased ability to metabolize AFB1 also. However, instead of the weakly mutagenic AFQ1 metabolite seen with the PB-microsomes, large amounts of the strongly mutagenic AFM1 metabolite was formed. Although AFM1 is not known to be a direct mutagen, it was highly mutagenic upon activation with microsomes. The very steep dose-related increases of mutagenicity and appearance of bacterial toxicity at relatively lower doses of AFB1 may have been caused by the secondary metabolic activation. The ability of BHA-microsomes to metabolize AFB1 was decreased. Among the metabolites produced by the BHA-microsomes, the non-mutagenic AFB2a was formed in significantly increased amounts but the toxic AFB-8,9-epoxide was produced only in much reduced amounts. The AFB2a was not mutagenic even after metabolic activation with microsomes. When increasing concentrations of AFB1 was incubated with BHA-microsomes, a very mild dose-related increases of mutagenicity was observed and the occurence of toxic effects on bacterial growth appeared only at high doses of AFB1. This may have been due both to the reduced rate of overall AFB1 metabolism and to the decreased formation of the highly mutagenic AFB-8,9-epoxide but an increased formation of the non-mutagenic AFB2a metabolite by the BHA-microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)  (+info)

Reactive oxygen species are not required for an arsenic trioxide-induced antioxidant response or apoptosis. (62/170)


Antioxidant butylated hydroxyanisole inhibits estrogen-induced breast carcinogenesis in female ACI rats. (63/170)


Effects of phenolic antioxidants in low dose combination on forestomach carcinogenesis in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine. (64/170)

The combined effects of low doses of promoters or carcinogens on two-stage forestomach carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine. Groups of 15 rats were given a single 150 mg/kg body weight intragastric dose of N-methyl-N'-nitro-N-nitrosoguanidine. Starting 1 week later they were fed a diet containing low doses of known forestomach promoters/carcinogens (0.5% caffeic acid, 0.2% catechol, 0.5% butylated hydroxyanisole, or 0.25% 2-tert-butyl-4-methylphenol), alone or in combination, or basal diet without antioxidant supplement for 35 weeks. Histopathological examination revealed the incidences of forestomach squamous cell carcinomas in animals treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by caffeic acid, catechol, butylated hydroxyanisole, 2-tert-butyl-4-methylphenol, and basal diet to be 27, 20, 13, 13, and 7%, respectively, whereas the incidence increased to 80% by the combined treatment with these four chemicals. The present results thus show that although the low doses of individual promoters/carcinogens did not have significant promoting activity, their combination exerted a strong enhancing influence on rat forestomach carcinogenesis. The findings indicate the importance of summation and synergism at a low dose for agents present in the human environment.  (+info)