The contamination of valsartan and other sartans, Part 2: Untargeted screening reveals contamination with amides additionally to known nitrosamine impurities

Scherf‐Clavel, Maike; Kinzig, Martina; Besa, Axel; Schreiber, André; Bidmon, Clemens; Abdel‐Tawab, Mona; Wohlfart, Jonas; Sörgel, Fritz; Holzgrabe, Ulrike

doi:10.1016/j.jpba.2019.04.035

Cited by 44 publications

(24 citation statements)

References 9 publications

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“…It also contaminates many public water supplies as a result of certain water treatment processes (Richardson, 2003;Kimoto, 1980;Sedlak et al, 2005;Mitch and Sedlak, 2004). Furthermore, a recent public health crisis has emerged due to high levels of NDMA contamination in commonly used drugs taken by millions of people (Pottegå rd et al, 2018;Scherf-Clavel et al, 2019;Sö rgel et al, 2019;Tsutsumi et al, 2019;Parr and Joseph, 2019). While O 6 MeG lesions are known to be mutagenic and have been intensely studied, 3MeA lesions are also highly consequential, but less well studied.…”

Section: Introductionmentioning

confidence: 99%

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

et al. 2021

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“…Sartan substances are one of the most frequently prescribed antihypertensive drugs and have been widely applied in the treatment of cardiovascular diseases all over the world (Muszalska et al 2014). In the production process of sartan products, organic solvents containing amide groups might form secondary amines in acidic solution at high temperature, and then react with nitrous acid, thereby leading to the formation of N-nitrosamines (Scherf-Clavel et al 2019). Since this reaction probably occurred in syntheses of various sartan substances, many kinds of N-nitrosamines might be found in the sartan products.…”

Section: Introductionmentioning

confidence: 99%

Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances

Liu¹,

Xie²,

Mai

et al. 2021

J Anal Sci Technol

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Recently, N-nitrosamines have been unexpectedly found in generic sartan products. Herein, we developed a sensitive and stable GC-MS/MS method with multiple reactions monitoring mode for the simultaneous determination of four N-nitrosamines in sartan substances, namely, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, and N-nitrosodiisopropylamine. The conditions of gas chromatography and mass spectrometry were optimized. The method was validated according to the International Council for Harmonization guidelines in terms of sensitivity, linearity, accuracy, precision, specificity, and stability. The limits of detection of N-nitrosamines in sartan substances ranged from 0.002 to 0.150 ppm, and the corresponding limits of quantification were in the range of 0.008-0.500 ppm, which met the sensitivity requirements for the limits set by the Food and Drug Administration of the United States. The internal standard curve of four N-nitrosamines showed good linearity of regression coefficients over 0.99. The recoveries of N-nitrosamines in selected sartan drugs ranged from 87.68 to 123.76%. The intraday and interday relative standard deviation values were less than 9.15%. Therefore, this proposed method exhibited good sensitivity and precision, high accuracy, and fast analysis speed, which provide a reliable method for quality control of N-nitrosamines in sartan products.

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“…It also contaminates many public water supplies as a result of certain water treatment processes (Kimoto, 1980; Mitch and Sedlak, 2004; Richardson, 2003; Sedlak et al, 2005). Furthermore, a recent public health crisis has emerged due to high levels of NDMA contamination in commonly used drugs taken by millions of people (Parr and Joseph, 2019; Pottegard et al, 2018; Scherf-Clavel et al, 2019; Sorgel et al, 2019; Tsutsumi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

Kay

Corrigan

Armijo

et al. 2021

Preprint

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SummaryN-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag−/− and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found that unrepaired 3MeA is somewhat toxic but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.

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The contamination of valsartan and other sartans, Part 2: Untargeted screening reveals contamination with amides additionally to known nitrosamine impurities

Cited by 44 publications

References 9 publications

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

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