Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers.

Hinchman, Cheri A.; Matsumoto, Hiromu; Simmons, Thomas W.; Ballatori, Nazzareno

doi:10.1016/s0021-9258(18)54551-8

Cited by 101 publications

(25 citation statements)

References 42 publications

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“…DNP-C is reabsorbed by cells and further metabolized to the mercapturic acid form (DNP-NAC) (Cooper and Hanigan 2018;Dilda et al 2008;Garnier et al 2014;Hinchman et al 1998). The formation of the mercapturate was observed in previous studies focusing on the metabolic capacity of rodents, fish and mollusk (Hinchman et al 1991;Simmons et al 1991;Trevisan et al 2016). Considering the fact that we observed DNP-NAC in our study suggests that the intermediate products have been formed as well, for lack of alternative pathways leading to the mercapturate, but evaded detection due to their low concentration or short-lived nature.…”

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 90%

“…Studies in mammalian systems report a fast uptake and a rapid biotransformation of CDNB (Hinchman et al 1991;Jewell et al 2000;Villanueva et al 2006;Wahllander and Sies 1979).…”

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

“…In our study, those intermediate products of the mercapturic acid pathway could not be detected. Though never tested before in zebrafish, some previous studies describe the formation of DNP-CG and DNP-C in different systems, such as isolated liver perfusions and mollusks (Hinchman et al 1991;Simmons et al 1991;Trevisan et al 2016;Vaidya and Gerk 2007). Those studies, however, used higher CDNB concentrations and different dosing systems.…”

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

“…However, the y-glutamyl transferase activity and organ distribution vary considerably between species thereby influencing whether the formed glutathione conjugate is biotransformed on-site to mercapturic acid or transported further via circulatory systems (Hinchman and Ballatori 1994). Furthermore, the proportion of each biotransformation product in relation to the overall chemical load depends on the parent compound itself and the concentration applied (Hinchman et al 1991). At comparable CDNB concentrations (61 and 101 ng/ml, 0.30 and 0.50 µM respectively), skate and rat livers excreted > 50% of total hepatic biotransformation products as DNP-SG, whereas in guinea pigs DNP-NAC represented the highest proportion of hepatic DNP-conjugates Simmons et al 1991).…”

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

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Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

Tierbach

Groh

Schönenberger

et al. 2020

Toxicological Sciences

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Zebrafish (Danio rerio) early life stages offer a versatile model system to study the efficacy and safety of drugs or other chemicals with regard to human and environmental health. This is because, aside from the well-characterized genome of zebrafish and the availability of a broad range of experimental and computational research tools, they are exceptionally well suited for high-throughput approaches. Yet, one important pharmacokinetic aspect is thus far only poorly understood in zebrafish embryo and early larvae: their biotransformation capacity. Especially, biotransformation of electrophilic compounds is a critical pathway because they easily react with nucleophile molecules, such as DNA or proteins, potentially inducing adverse health effects. To combat such adverse effects, conjugation reactions with glutathione and further processing within the mercapturic acid pathway have evolved. We here explore the functionality of this pathway in zebrafish early life stages using a reference substrate (1-chloro-2,4-dinitrobenzene, CDNB). With this work, we show that zebrafish embryos can biotransform CDNB to the respective glutathione conjugate as early as 4 h postfertilization. At all examined life stages, the glutathione conjugate is further biotransformed to the last metabolite of the mercapturic acid pathway, the mercapturate, which is slowly excreted. Being able to biotransform electrophiles within the mercapturic acid pathway shows that zebrafish early life stages possess the potential to process xenobiotic compounds through glutathione conjugation and the formation of mercapturates. The presence of this chemical biotransformation and clearance route in zebrafish early life stages supports the application of this model in toxicology and chemical hazard assessment.

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Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 90%

“…Studies in mammalian systems report a fast uptake and a rapid biotransformation of CDNB (Hinchman et al 1991;Jewell et al 2000;Villanueva et al 2006;Wahllander and Sies 1979).…”

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

Section: Mercapturic Acid Pathway Is Functional In Zebrafish Early Life Stagesmentioning

confidence: 99%

See 2 more Smart Citations

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

Tierbach

Groh

Schönenberger

et al. 2020

Toxicological Sciences

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show abstract

“…The GSTs are a family of enzymes that plays a major role in detoxification of electrophilic compounds, such as drugs and environmental pollutants, by catalyzing the conjugation reaction of the electrophilic moiety with glutathione (GSH). Connected to this major role in phase II metabolism, the level of GST activity is frequently used to define the biotransformation capacity of biological test systems. , …”

Section: Introductionmentioning

confidence: 99%

LC-APCI(−)-MS Determination of 1-Chloro-2,4-dinitrobenzene, a Model Substrate for Glutathione S-Transferases

Tierbach

Groh

Schönenberger

et al. 2020

J. Am. Soc. Mass Spectrom.

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1-Chloro-2,4-dinitrobenzene (CDNB) is widely used as a model substrate for measuring enzyme activity of glutathione S-transferases in toxicity studies and in studies focusing on the metabolic capacity of different test systems. To allow the quantification of CDNB at low, non-toxic concentrations, we developed a sensitive liquid chromatography-mass spectrometry (LC-MS) technique, which is based on electron capture ionization using atmospheric pressure chemical ionization (APCI) in negative ion mode. Gas phase reactions occurring under atmospheric pressure produce specific ions that allow direct CDNB quantification down to 17 ng/ml in water. Using the new technique, we were able to verify CDNB exposure concentrations applied in two typical toxicity studies with early life stages of the common model organisms, zebrafish (Danio rerio) and a zebrafish embryonic cell line (Pac2).

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Overview of Glutathione Function and Metabolism

Will

1999

CP Toxicology

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Glutathione is a key player in reduction processes in the cell. It is responsible for maintaining thiol groups of intracellular proteins by providing reducing power for cysteine, dihydolipoate, CoA, ascorbate, and vitamin E. It also plays a role in reduction of NTPs to dNTPs. Glutathione is also involved in detoxification of endogenous and exogenous compounds, participates in the synthesis of leukotrienes and prostaglandins, serves as a cofactor for various enzymes, stores and transports cysteine, and may be involved in cell cycle regulation and thermotolerance.

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Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers.

Cited by 101 publications

References 42 publications

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

LC-APCI(−)-MS Determination of 1-Chloro-2,4-dinitrobenzene, a Model Substrate for Glutathione S-Transferases

Overview of Glutathione Function and Metabolism

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