Evidence Of Genotoxic Activity Research Articles

Genotoxicity assessment of S-equol in bacterial mutation, chromosomal aberration, and rodent bone marrow micronucleus tests

Intervention studies in man have shown that dietary soy isoflavones may provide certain health benefits. One of the possible reasons for this benefit is that the daidzein contained in soy is converted to S-equol. As part of a drug development program for S-equol, three genotoxicity studies were conducted. The studies comprised bacterial mutation, chromosomal aberration, and in vivo bone marrow micronucleus tests conducted according to Good Laboratory Practices (GLP). No evidence of genotoxic activity was observed in the in vitro tests at concentrations up to those associated with cell toxicity. In addition, no evidence of cytotoxicity or genotoxicity was seen in the rat bone marrow micronucleus test in animals dosed at levels up to the standard limit of 2000 mg/kg. It is concluded that S-equol is not active in the standard battery of genotoxicity assays recommended by the International Conference on Harmonisation (ICH) for registration of new pharmaceuticals. The current results support the further development of S-equol.

Safety evaluation of α-lipoic acid (ALA)

The safety of the antioxidant α-lipoic acid (racemic form) (ALA), also called thioctic acid (CAS RN 1077-28-7) was assessed in acute and subchronic toxicity studies as well as in in vitro and in vivo mutagenicity/genotoxicity studies. ALA was not acutely toxic to rats (LD 50 > 2000 mg/kg bw, OECD method 425). Administration of 31.6 or 61.9 mg ALA/kg bw/day for 4 weeks to male/female Wistar rats did not show any adverse effects. Specifically, there was no significant difference between control and treated animals at 31.6 or 61.9 mg ALA/kg bw with regard to body weight gain, feed consumption, animal behaviour, or haematological and clinical chemistry parameters. Only the high-dose of 121 mg ALA/kg bw was associated with slight alterations in liver enzymes as well as histopathological effects on the liver and mammary gland. ALA did not possess any mutagenic activity in the Ames assays conducted with various bacterial strains of Salmonella typhimurium. Moreover, there was no evidence of genotoxic activity in a mouse micronucleus assay. The results of these studies support the safety of ALA. The no-observed-adverse-effect level (NOAEL) is considered to be 61.9 mg/kg bw/day.

New drugs—reports of new drugs recently approved by the FDA lamivudine

Several 2′,3′-dideoxynucleosides are potential inhibitors of HIV. In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines using standard susceptibility assays. IC 50 values were in the range of 2 nM to 15 μM. Lamivudine has anti HIV-1 activity in all acute virus-cell infections tested. Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in adult patients was ∼ 86% for the tablet and ∼ 87% for the oral solution. After oral administration of 2 mg/kg twice a day, the peak serum lamivudine concentration was ∼ 1.5 μg/mL. The AUC and C max increased in proportion to oral dose over the range 0.25–10 mg/kg. Lamivudine is also active against zidovudine-resistant clinical isolates of HIV. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine. The lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolism of lamivudine is the trans-sulfoxide metabolite in the urine. The majority of lamivudine is eliminated unchanged in urine. The recommended oral dose of lamivudine for adult is 150 mg twice a day administered in combination with zidovudine. In genetic toxicology tests, lamivudine, like many other nucleoside analogue, has shown evidence of weak activity in in vitro cytogenic assays and the mouse lymphoma assay. However, no evidence of genotoxic activity was seen when the racemate was examined in the rat bone marrow micronucleus test and the rat liver UDS test using doses of up to 600 mg/kg by the iv route. Negative results have also been obtained in an in vitro cell transformation assay using Balb/3T3 cells. Epivir™ tablets are for oral administration. Each tablet contains 150 mg of lamivudine and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Epivir™ Oral Solution is for oral administration. One milliliter of Epivir™ Oral Solution contains 10 mg of lamivudine (6% v/v), methylparaben, propylene glycol, propylparaben, and sucrose.

Covalent binding of 1,1,1,2‐tetrachloroethane to nucleic acids as evidence of genotoxic activity

Twenty-two hours after ip administration to male Wistar rats and BALB/c mice, 1,1,1,2-tetrachloroethane (1,1,1,2-TTCE) is bound covalently to DNA, RNA, and proteins of liver, lung, kidney, and stomach. The in vivo reactivity leads to binding values to DNA generally higher in mouse organs than in rat organs. The covalent binding index (CBI) values (82 in mouse liver DNA and 40 in rat liver DNA) classify 1,1,1,2-TTCE as a weak to moderate initiator. Both microsomal and cytosolic enzymatic systems from rat and mouse organs are capable of bioactivating 1,1,1,2-TTCE in vitro. Liver fractions are the most effective. When the activating systems are simultaneously present in the incubation mixture a synergistic effect is observed. Unlike the related chemical 1,1,2,2-tetrachloroethane (1,1,2,2-TTCE), which is bioactivated only through an oxidative route, 1,1,1,2-TTCE metabolism is carried on by oxidative and reductive pathways, both dependent on cytochrome P-450. 1,1,1,2-TTCE is also bioactivated by microsomal GSH-transferases from liver and lung. These data further confirm that correlations exist between structure and genotoxic activity of halocompounds.

Genotoxicity studies with a blend of zinc dialkyldithiophosphate lubricant additives

The mutagenic activity of a blend of primary zinc dialkyldithiophosphate lubricant additives suspended in process oils and a blend of the process oils alone was investigated in agar layer cultures of Salmonella typhimurium TA1535, TA1537, TA1538, TA98 and TA100, both with and without the incorporation of a rat liver microsomal activation system (S9). Zinc dimethyldithiocarbamate was tested as a structurally-related model bacterial mutagen, and, in additional control experiments, the mutagenic activity of zinc dimethyldithiocarbamate and benzo[ a]pyrene was investigated in combination with the blend of process oils in selected bacterial tester strains. Transformation frequencies of BHK cells were determined by colony growth in soft agar culture following treatment with a blend of the zinc dialkyldithiophosphate lubricant additives suspended in process oils, a blend of the process oils, 7,12-dimethylbenzanthracene, both in the presence and in the absence of a blend of the process oils, or zinc dimethyldithiocarbamate. All experiments incorporated a rat liver microsomal activation system (S9). Application of a blend of the zinc dialkyldithiophosphate additives or a blend of the process oils used in their manufacture did not increase the reverse mutation frequencies of Salmonella typhimurium TA1535, TA1537, TA1538, TA98 or TA100, or significantly increase the transformation frequency of BHK cells under the experimental conditions described. Zinc dimethyldithiocarbamate increased the reverse mutation frequency in some bacterial tester strains, but did not significantly increase the transformation frequency of BHK cells under the described experimental conditions. The addition of the blend of the process oils in combination with the control materials, zinc dimethyldithiocarbamate or benzo[ a]pyrene had an inhibitory effect on the mutagenic activity at high doses of each in the bacterial assays, and in the BHK assay the transforming ability of 7,12-Dimethylbenzanthracene was suppressed in the presence of the blend of the process oils. Thus, the additive materials showed on evidence of genotoxic activity in the bacterial mutation assays, or in the BHK transformation assay under the experimental conditions describe.