The mutagenic activity of quercetin for Salmonella typhimurium TA98 was inhibited by addition of metal salts. MnCl2 was a potent inhibitor, followed by CuCl2, FeSO4, and FeCl3, the probable mechanism being facilitated catalytic oxidation of quercetin. With quercetin incorporated at a level of 100 nmoles/plate, approximate doses (nmoles/plate) to give 50% inhibition of mutagenic activity were: MnCl2 less than 10 (-S9), 18 (+S9); CuCl2 65 (-S9), greater than 100 (+S9); FeSO4 190 (-S9), greater than 300 (+S9); or FeCl3 275 (-S9), greater than 300 (+S9). Ascorbate, superoxide dismutase, and, to a lesser extent, NADH and NADPH, all enhanced the mutagenic activity of quercetin in the absence of the mammalian-microsome (S9) system, but had no significant effect in the presence of the S9 mix. The maximum enhancement of activity by ascorbate or superoxide dismutase was approximately 87% of the increase achieved by addition of the S9 mix. Tyrosinase (catechol oxidase) substantially reduced the mutagenic activity of quercetin in the absence of the S9 mix. At lower levels of tyrosinase, activity was restored by incorporation of the S9 mix. It is proposed that the S9 mix enhances the mutagenic activity of quercetin by scavenging superoxide radicals, thus inhibiting the autoxidation of quercetin, and possibly by reducing quinone oxidation products of quercetin. The mutagenic activity of quercetin increased substantially when the pH of the media was decreased. This may be due in part to a decrease in ionization of quercetin at lower pH, thereby increasing its absorption by the tester strain, to a decrease in the rate of autoxidation of quercetin at lower pH, or to a combination of these.

Antioxidants↗

PubMedDate not supplied

Role of tryptophan metabolites in urinary bladder cancer.

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Animals↗

PubMedDate not supplied

Correlation between N-acetyltransferase activities in uroepithelia and in vivo acetylator phenotype.

The relationship between in vivo acetylator phenotype of individuals and N-acetyltransferase (NAT) activity in the cytosol of their cultured uroepithelia was examined in four urology patients. In vivo acetylator phenotypes were assigned by determining the ratio of N-acetyl vs. total [N-acetyl+free] sulfamethazine in urine and blood following a single oral dose (1 gm) of sulfamethazine. From the same patients, a surgical specimen of the ureter was obtained, uroepithelial cells were cultured in vitro, and the cytosols prepared. NAT activities were determined by measuring the amount of 4-acetylaminobiphenyl formed from incubation of uroepithelial cytosol with the substrate, 4-aminobiphenyl, and the cofactor [14C]acetyl coenzyme A. The two individuals phenotyped as "slow acetylators" by the in vivo method had NAT activities of 8.3 and 16.2 pmol 4-acetylaminobiphenyl/mg protein/min. In contrast, the two individuals phenotyped as "rapid acetylators" showed activities of 50.9 and 109.5 pmol 4-acetylaminobiphenyl/mg protein/min. The rapid acetylators exhibit about 6-fold greater uroepithelial NAT activities than slow acetylators, thus showing a direct correlation between the NAT activity in the uroepithelium, the target tissue of the human bladder carcinogen 4-aminobiphenyl, and the in vivo acetylator phenotype. These results imply that susceptibility of individuals to arylamine-induced bladder cancer might be associated with NAT activities in their target cells and that in vivo acetylator phenotyping could serve as a useful and relevant biochemical screening marker to assess the risk of developing bladder cancer.

Acetylation↗

PubMedDate not supplied

Metabolism and disposition of N-(4-(5-nitro-2-furyl)-(2-14-C)thiazolyl)acetamide in the rat.

The metabolism of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), a carcinogen for the mouse, rat, dog, and hamster, was investigated in the rat. Radioactive NFTA administered ip to young and lactating female rats was rapidly absorbed through the peritoneum and deposited in the urine, intestinal contents, and feces. Less than 0.5% of the radioactivity was expired as CO2 during the first 24 hr. Two yellow metabolites, accounting for 5 and 27% of the radioactivity in the urine, were found by paper chromatography. One metabolite retained the 2-amino-4-(5-nitro-2-furyl)thiazole moiety. Less than 0.5% of the radioactivity in the urine was due to unchanged 14-C-NFTA. The radioactivity level in the visceral organs reached a maximum 2 hr after dosing and then gradually decreased. Liver contained considerably more radioactivity than did other visceral organs; this was mainly distributed in the cytosol and 900g pellets. Fifty per cent of the radioactivity in the liver was bound to the hot trichloroacetic acid (TCA)-insoluble fraction; that bound to the cold TCA-insoluble fraction increased gradually from 66.9% at 2 hr to 82.6% at 24 hr. The radioactivity bound to the cold and hot TCA-insoluble fractions in kidney remained at 30% and 20%, respectively. Nitroreduction of 14-C-NFTA by microsomes, as a prerequisite of the binding of metabolite to microsomal protein, was demonstrated. Addition of L-cysteine or reduced glutathione to the incubation mixture did not alter the nitroreductase activity of the microsomes; however, binding of radioactivity to protein was significantly decreased. Addition of other amino acids did not significantly decrease the nitroreductase activity or binding to protein. These results suggest that reduced NFTA binds to the protein sulfhydryl groups. Since 14-C-NFTA binds to macromolecules in vivo,nitroreductionmay be important for the metabolism of 5-nitrofurans.

Acetamides↗