Cited by P13-23 A comparative analysis of the ability of various S9 compositions to metabolically activate N-nitrosamines to mutagens in the bacterial reverse mutation test

Optimizing the detection of N-nitrosamine mutagenicity in the Ames test DOI

Robert H. Heflich,

Michelle E. Bishop,

Roberta A. Mittelstaedt

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 153, P. 105709 - 105709

Published: Sept. 28, 2024

Language: Английский

Citations

A Comparative Analysis of Select P450 Enzymes in Uninduced and PB/BNF-Induced Hamster and Rat Liver S9 DOI

Kristie Evans,

Slaydon Boitnotte,

Errol Zeiger

et al.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Journal Year: 2025, Volume and Issue: 902, P. 503855 - 503855

Published: Feb. 1, 2025

Language: Английский

Citations

HESI GTTC Ring Trial: Concordance between Ames and Rodent Carcinogenicity Outcomes for N-Nitrosamines (NAs) with Rat and Hamster Metabolic Conditions DOI

Joel P. Bercu, Alejandra Trejo‐Martin,

Connie L. Chen

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 105835 - 105835

Published: April 1, 2025

A multi-sector study (i.e., Ring Trial) was designed to improve the in vitro detection of N-nitrosamine (NA)-associated mutagenicity by optimizing bacterial reverse mutation Ames) assay protocol and testing various conditions on sensitivity specificity for prediction rodent carcinogenicity. total 29 NAs 3 N-nitroso drug-like compounds from different structural classes carcinogenicity outcomes were tested (two independent laboratories per compound) across 5 strains using a 30-minute pre-incubation protocol. To evaluate impact metabolic activating systems (MASs), included use 10 or 30% liver S9 fractions prepared rats hamsters pretreated with inducers enzymatic activity. Results indicate that E. coli Salmonella typhimurium detecting single base pair mutations, coupled MASs containing hamster S9s most sensitive (90%) identifying are carcinogens. Regarding MAS combinations, highest rat (93%), but has low (45%), good laboratory agreement Ames calls (91%). DMSO water considered suitable solvents, except small-molecular weight alkyl NAs. These results will support harmonized NAs, giving high confidence negative result.

Language: Английский

Citations

Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential DOI

Jennifer Cheung, Krista L. Dobo, Shaofei Zhang

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2024, Volume and Issue: 65(6-7), P. 203 - 221

Published: July 1, 2024

Abstract Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas interest for companies health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels N ‐nitrosamine drug substance‐related impurities (NDSRIs) using SAR, however some compounds require experimental data support derivation a recommended AI. Many angiotensin‐converting enzyme inhibitors, identified by suffix “pril,” have secondary amines that can potentially react form nitrosamines. Here we consider structural assessment metabolism data, coupled comprehensive vitro vivo (mouse) genotoxicity testing evaluate this particular class ‐nitroso ramipril quinapril, both which predicted inhibited nitrosamine bioactivation due steric hinderance branching at α‐position were non‐genotoxic liver comet assay non‐mutagenic Big Blue® mutation duplex sequencing assays. Predicted along quantum chemical calculations related DNA interactions offer molecular basis negative results observed testing. These concluded be non‐carcinogenic; therefore, they should controlled according ICH Q3B guidance. Furthermore, these quinapril considered when evaluating appropriate AI control strategy other structurally similar “pril” NDSRIs.

Language: Английский

Citations

An Enhanced Metabolization Protocol for In Vitro Genotoxicity Assessment of N‐Nitrosamines in Mammalian Cells DOI

Marit E. Geijer,

A. M. Gernaat,

Nynke Moelijker

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

ABSTRACT N‐Nitrosamines (NAs) are probable human carcinogens and were detected as impurities in pharmaceuticals, which led to a concern for health. NAs require metabolic activation before they become mutagenic, not all mutagenic since their reactivity is related structure. While some potent mutagens vivo, vitro metabolization with exogenous S9 liver extract generally less efficient. an enhanced bacterial mutagenicity protocol was recently developed, uses increased concentrations of extracts, there presently improved suitable mammalian cell genotoxicity assays. Therefore, we optimized hamster extract‐based NA assessed the genotoxic potential various using ToxTracker. With this (EMP), potency N‐nitrosodimethylamine (NDMA) approximately 200‐fold compared standard exposure The EMP further validated seven additional humans commonly exposed: N‐nitrosodiethylamine (NDEA), N‐nitrosodiethanolamine (NDELA), N‐nitrosodibutylamine (NDBA), N‐nitrosofluoxetine (NF), 1‐nitrosopyrrolidine (NPYR), N‐nitrosomorpholine (NMOR), 1‐cyclopentyl‐4‐nitrosopiperazine (CPNP), two non‐mutagenic NAs: N‐nitrosobupropion (NBuPRO) N‐nitrosoproline (NPRO). Genotoxicity could be confirmed six EMP, demonstrating that cells new approach methodology (NAM) ToxTracker may have when investigating NA‐related genotoxicity.

Language: Английский

Citations

Selection of Solvent and Positive Control Concentration for Enhanced Ames Test Conditions for N-Nitrosamine Compounds DOI

Chetan K. Kajavadara, Satyam N. Patel, Rushikesh M. Shukla

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 154, P. 105711 - 105711

Published: Oct. 10, 2024

Language: Английский

Citations

P13-23 A comparative analysis of the ability of various S9 compositions to metabolically activate N-nitrosamines to mutagens in the bacterial reverse mutation test DOI

Frank Bringezu, Stéphanie Simon,

J Dieckhoff

et al.

Toxicology Letters, Journal Year: 2024, Volume and Issue: 399, P. S219 - S219

Published: Sept. 1, 2024

Language: Английский

Citations