Katarzyna Regulska1, Marek Murias2, Beata Stanisz3, Miłosz Regulski2. 1. Greater Poland Cancer Center, 15th Garbary Street, 61-866 Poznan, Poland ; Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland. 2. Poznan University of Medical Sciences, Chair and Department of Toxicology, 30th Dojazd Street, 60-631 Poznan, Poland. 3. Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland.
Abstract
AIM: The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. BACKGROUND: IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. MATERIALS AND METHODS: Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit. RESULTS: None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds. CONCLUSIONS: The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.
AIM: The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. BACKGROUND: IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. MATERIALS AND METHODS: Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit. RESULTS: None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds. CONCLUSIONS: The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.
Authors: P A Escobar; R A Kemper; J Tarca; J Nicolette; M Kenyon; S Glowienke; S G Sawant; J Christensen; T E Johnson; C McKnight; G Ward; S M Galloway; L Custer; E Gocke; M R O'Donovan; K Braun; R D Snyder; B Mahadevan Journal: Mutat Res Date: 2012-12-20 Impact factor: 2.433
Authors: Yet Hua Loh; Paula Jakszyn; Robert N Luben; Angela A Mulligan; Panagiota N Mitrou; Kay-Tee Khaw Journal: Am J Clin Nutr Date: 2011-03-23 Impact factor: 7.045