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Omeprazole does not bind to DNA nor does it induce unscheduled DNA synthesis (UDS) in parietal cells
119 Evaluation of the genotoxicity of 4-diethylamino4'.nitroazobenzene and seven analogues
A series of 8 nitroazo compounds based on 4-diethylamino-4'-nitroazobenzene has been examined for genotoxic activity in a collaborative study under the auspices of the Ecological and Toxicological Association of Dyestuffs Manufacturers (ETAD). The evaluation has been conducted in two parts, firstly an examination in vitro to assess for any intrinsic genotoxic activity of the compound. The chemicals were examined in the Ames test in a standard plate assay both with and without $9, and in a minimum of the four tester strains recommended in the OECD guideline for this assay, TA1535, TA1537, TA98 and TA100. All of the compounds were mutagenic in the Ames test in one or more of the Salmonella tester strains, and all were positive in TA98 with $9. A considerable range of potency was seen, from compounds proving just positive to ones that were very strongly positive. The chemicals were further examined in vitro for mammalian cell gene mutation at either the HGPRT or the TK locus in a standard (CHO, V79 or L5178Y) cell system. Only one of the chemicals was mutagenic and only with $9. This chemical also showed the most potent response in the Ames test. The second part of the study was an examination in vivo to see whether any activity was expressed in the whole animal. The in vivo rat liver DNA repair (UDS) assay was chosen as being the most likely to be sensitive to aromatic nitroazo compounds. All of the materials were negative when tested alongside a structurally related positive control. A number of chemicals were further examined in the mouse bone marrow micronucleus assay and these too were negative.
10 Frandsen, H., S. Grivas 1, L. Dragsted and J.C. Larsen, Institute of Toxicology, National Food Agency, M~rkhcj Bygade 19, DK-2860 Scborg (Denmark) and ~ Department of Chemistry, Swedish University of Agricultural Sciences, Uppsala (Sweden)
DNA adducts formed by the food mutagen 2amino- 1-methyl-6-phenylimidazo [4,5 -b ] pyridine (PhlP) in vitro and in vivo. Identification of a PhlP-2-deoxyguanosine adduct The direct acting mutagenic metabolite of the food mutagen 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) does not react with DNA. Upon acetylation of the N-hydroxy-PhlP with acetic anhydride two products could be detected. MS analysis showed that both products were monoacetyl derivatives of N-OH-PhlP. One of the products did not show any reactivity towards DNA and is probably the N-acetyl derivative of N-OH-PhlP. The other product, which is most likely to be the O-acetyl derivative of N-OH-PhlP, reacted with DNA and 2-deoxyguanosine but not with 2-deoxycytidine, 2-deoxyadenosine or 2-deoxythymidine. HPLC analysis of enzymatically hydrolyzed calf thymus DNA which had been reacted with N-acetoxy-PhlP showed one adduct which was chromatographically and spectroscopically identical to an adduct obtained from reaction between N-acetoxy-PhlP and 2-deoxyguanosine. Hydrolysis of liver DNA from rats dosed with 3H-PhlP showed one adduct, which was chromatographically identical to the synthetic PhlP-2-deoxyguanosine adduct. The results show that PhlP upon metabolic activation reacts with DNA forming a PhlP-2-deoxyguanosine adduct. This adduct has been purified and characterized by mass spectral and ~HNMR analysis, showing that PhlP, in contrast to other cooked food mutagens, has not reacted with C-8 in guanine. Final confirmation of the structure awaits t3C-NMR analysis.
11 Fryklund, J., A.-K. Falkn~is, S. Ottosson and H.F. Helander, AB H~issle, Preclinical Research, S-431 83 M61ndal (Sweden) Omeprazole does not bind to DNA nor does it induce unscheduled DNA synthesis (UDS) in parietal cells Omeprazole is converted in the acidic canaliculi of the parietal cells (PC) to a sulphenamide derivative which binds to the H+,K+-ATPase and
A series of 8 nitroazo compounds based on 4-diethylamino-4'-nitroazobenzene has been examined for genotoxic activity in a collaborative study under the auspices of the Ecological and Toxicological Association of Dyestuffs Manufacturers (ETAD). The evaluation has been conducted in two parts, firstly an examination in vitro to assess for any intrinsic genotoxic activity of the compound. The chemicals were examined in the Ames test in a standard plate assay both with and without $9, and in a minimum of the four tester strains recommended in the OECD guideline for this assay, TA1535, TA1537, TA98 and TA100. All of the compounds were mutagenic in the Ames test in one or more of the Salmonella tester strains, and all were positive in TA98 with $9. A considerable range of potency was seen, from compounds proving just positive to ones that were very strongly positive. The chemicals were further examined in vitro for mammalian cell gene mutation at either the HGPRT or the TK locus in a standard (CHO, V79 or L5178Y) cell system. Only one of the chemicals was mutagenic and only with $9. This chemical also showed the most potent response in the Ames test. The second part of the study was an examination in vivo to see whether any activity was expressed in the whole animal. The in vivo rat liver DNA repair (UDS) assay was chosen as being the most likely to be sensitive to aromatic nitroazo compounds. All of the materials were negative when tested alongside a structurally related positive control. A number of chemicals were further examined in the mouse bone marrow micronucleus assay and these too were negative.
10 Frandsen, H., S. Grivas 1, L. Dragsted and J.C. Larsen, Institute of Toxicology, National Food Agency, M~rkhcj Bygade 19, DK-2860 Scborg (Denmark) and ~ Department of Chemistry, Swedish University of Agricultural Sciences, Uppsala (Sweden)
DNA adducts formed by the food mutagen 2amino- 1-methyl-6-phenylimidazo [4,5 -b ] pyridine (PhlP) in vitro and in vivo. Identification of a PhlP-2-deoxyguanosine adduct The direct acting mutagenic metabolite of the food mutagen 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) does not react with DNA. Upon acetylation of the N-hydroxy-PhlP with acetic anhydride two products could be detected. MS analysis showed that both products were monoacetyl derivatives of N-OH-PhlP. One of the products did not show any reactivity towards DNA and is probably the N-acetyl derivative of N-OH-PhlP. The other product, which is most likely to be the O-acetyl derivative of N-OH-PhlP, reacted with DNA and 2-deoxyguanosine but not with 2-deoxycytidine, 2-deoxyadenosine or 2-deoxythymidine. HPLC analysis of enzymatically hydrolyzed calf thymus DNA which had been reacted with N-acetoxy-PhlP showed one adduct which was chromatographically and spectroscopically identical to an adduct obtained from reaction between N-acetoxy-PhlP and 2-deoxyguanosine. Hydrolysis of liver DNA from rats dosed with 3H-PhlP showed one adduct, which was chromatographically identical to the synthetic PhlP-2-deoxyguanosine adduct. The results show that PhlP upon metabolic activation reacts with DNA forming a PhlP-2-deoxyguanosine adduct. This adduct has been purified and characterized by mass spectral and ~HNMR analysis, showing that PhlP, in contrast to other cooked food mutagens, has not reacted with C-8 in guanine. Final confirmation of the structure awaits t3C-NMR analysis.
11 Fryklund, J., A.-K. Falkn~is, S. Ottosson and H.F. Helander, AB H~issle, Preclinical Research, S-431 83 M61ndal (Sweden) Omeprazole does not bind to DNA nor does it induce unscheduled DNA synthesis (UDS) in parietal cells Omeprazole is converted in the acidic canaliculi of the parietal cells (PC) to a sulphenamide derivative which binds to the H+,K+-ATPase and