Genotoxicity of 2-bromo-3′-chloropropiophenone

• Published in: Toxicology and applied pharmacology Vol. 270; no. 2; pp. 158 - 163
• Main Authors: Meng, Fanxue, Yan, Jian, Li, Yan, Fu, Peter P., Fossom, Linda H., Sood, Ramesh K., Mans, Daniel J., Chu, Pei-I, Moore, Martha M., Chen, Tao
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15-07-2013; Elsevier
• Subjects: 2-Bromo-3′-chloropropiophenone; 60 APPLIED LIFE SCIENCES; Acetylcysteine - pharmacology; Ames test; ANTIOXIDANTS; Biological and medical sciences; Bupropion; Cell Line, Tumor; CYSTEINE; Drug Interactions; DRUGS; Genotoxicity; Humans; IMPURITIES; IN VITRO; In vitro micronucleus assay; Medical sciences; METABOLIC ACTIVATION; METABOLITES; Mutagenicity Tests - methods; N-Acetyl-l-cysteine; OXYGEN; Propiophenones - toxicity; SALMONELLA; TOXICITY; Toxicology; USA; N-Acetyl-l-cysteine; Bupropion; Ames test; 2-Bromo-3′-chloropropiophenone; In vitro micronucleus assay; Genotoxicity; Thiol; Micronucleus test; Psychotropic; Toxicity; Acetylcysteine; 2-Bromo-3'-chloropropiophenone; In vitro; Mucolytic; DNA; N-Acetyl-L-cysteine; Genotoxity test
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.04.012

Impurities are present in any drug substance or drug product. They can be process-related impurities that are not completely removed during purification or are formed due to the degradation of the drug substance over the product shelf-life. Unlike the drug substance, impurities generally do not have beneficial effects and may present a risk without associated benefit. Therefore, their amount should be minimized. 2-Bromo-3′-chloropropiophenone (BCP) is an impurity of bupropion, a second-generation antidepressant and a smoking cessation aid. The United States Pharmacopeia recommends an acceptable level for BCP that is not more than 0.1% of the bupropion. Because exposure to genotoxic impurities even at low levels is of significant concern, it is important to determine whether or not BCP is genotoxic. Therefore, in this study the Ames test and the in vitro micronucleus assay were conducted to evaluate the genotoxicity of BCP. BCP was mutagenic with S9 metabolic activation, increasing the mutant frequencies in a concentration-dependent manner, up to 22- and 145-fold induction over the controls in Salmonella strains TA100 and TA1535, respectively. BCP was also positive in the in vitro micronucleus assay, resulting in up to 3.3- and 5.1-fold increase of micronucleus frequency for treatments in the absence and presence of S9, respectively; and 9.9- and 7.4-fold increase of aneuploidies without and with S9, respectively. The addition of N-acetyl-l-cysteine, an antioxidant, reduced the genotoxicity of BCP in both assays. Further studies showed that BCP treatment resulted in induction of reactive oxygen species (ROS) in the TK6 cells. The results suggest that BCP is mutagenic, clastogenic, and aneugenic, and that these activities are mediated via generation of reactive metabolites.
•2-Bromo-3′-chloropropiophenone is an impurity of bupropion.•BCP was positive in both the Ames test and the in vitro micronucleus assay.•It induced high frequencies of mutations, micronuclei and hypodiploids.•It induced ROS and addition of NAC blocked the genotoxicity of BCP.•Its genotoxic action is possibly mediated via generation of reactive metabolites.