التفاصيل البيبلوغرافية
| العنوان: |
Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide. |
| المؤلفون: |
Gandhi, R. D., Hickert, S., Hoevelmann, Y., Mee, C. D., Schlingemann, J., Adams, A., Blanazs, A., Simon, S., Elloway, J., Rigger, L., Teasdale, A., Beaumont, C. V., Wright, L., Doherty, A. |
| المصدر: |
Archives of Toxicology; Dec2024, Vol. 98 Issue 12, p4159-4172, 14p |
| مصطلحات موضوعية: |
ESCHERICHIA coli, AMES test, BACTERIAL mutation, BIOTRANSFORMATION (Metabolism), MUTAGENS, FORMALDEHYDE |
| مصطلحات جغرافية: |
AMES (Iowa) |
| مستخلص: |
In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6–5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |