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Relationship: 2877

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Conjugation, GSH leads to Depletion, GSH

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Conjugation, GSH

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Depletion, GSH

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Glutathione conjugation leading to reproductive dysfunction via oxidative stress	adjacent	High	High	Leonardo Vieira (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
fish	fish	High	NCBI
mammals	mammals	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

GSH is an antioxidant generated in various kinds of cells, however, in vertebrates, this takes place mainly in liver cells, from where it is exported to other cell types (Lu 2013). Around 85% of free GSH is found in the cytoplasm, from where it is distributed to organelles such as mitochondria, which stores approximately 10% of the total GSH content, endoplasmic reticulum and extracellular space (Lu 2013; Aquilano, Baldelli, and Ciriolo 2014). Depletion of free GSH content happens because of the sulfhydryl group of the cysteine residue of this tripeptide reacts with xenobiotics during detoxification process, producing conjugates, which are secreted directly into the bile or converted to mercapturic acids and excreted into the urine, as well as due to the reaction with other reactive species as ROS. Nevertheless, unlike what happens to glycine and glutamate residues with oxidized glutathione (GSSG), which are recycled respectively from detoxification of xenobiotics and ROS-mediated oxidation, the cysteine molecule from GSH is excreted from the organism as a byproduct conjugated to the toxic molecule, causing, thereby, reduction of cellular levels of this limiting amino acid for the tripeptide production. In this way, restoration of regular intracellular GSH levels, via de novo synthesis and still from the reaction of reduction of oxidized glutathione (GSSG) ends up being hampered (X. Li 2009; Lushchak 2012; Gupta 2016; Aquilano, Baldelli, and Ciriolo 2014) and GSH levels are, consequently, depleted.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In vertebrate animals, chemicals such as ATZ (Egaas et al. 1993; Wiegand et al. 2001; Elia, Waller, and Norton 2002; Abel et al. 2004; McMullin et al. 2007; LeBlanc and Sleno 2011), DEM (Combes and Backof 1982; Kubal et al. 1995) and Hg (Stricks and Kolthoff 1953; Valko, Morris, and Cronin 2005) are metabolized by GST through reduced GSH-binding in phase II of biotransformation, generating GSH conjugates.

In vitro and in vivo data reveal that ATZ leads to GSH depletion through that pathway in various fish species. For instance, 25 μg/mL of this chemical uses up GSH neutrophil in common carp after 2 – 3 h of exposure (Wang et al. 2019). In young Prochilodus lineatus, after 24h of exposure at the concentrations of 2 and 10 μg/L, this herbicide did not display any effect on hepatic GSH levels, but, after 48 h, ATZ induced a significant decrease in the content of this biomarker (Santos and Martinez 2012). And in studies of acute toxicity, this chemical caused depletion of GSH level in both young catfish (Rhamdia quelen) (Mela et al. 2013) and in embryos of zebrafish (Danio rerio) (Adeyemi, da Cunha Martins-Junior, and Barbosa 2015) after 96 h of exposure, at the concentrations of 100 μg/L and 0.1 mM, respectively. Confirming these data, at longer exposures in adult female zebrafish, ATZ also underwent a decrease in ovary and liver GSH levels at concentrations above 1 and 10 μg/L, respectively, after 14 days of exposure (Jin et al. 2010). Similarly, common carp submitted to 1/5 of LC50 (96-h) of ATZ for 40 days, showed GSH levels significantly (p < 0.05) reduced in liver cells (Toughan et al. 2018).

As in fishes, this drop in GSH levels is also observed in different organs and tissues of mammals. Albino male rats orally treated with ATZ (200 mg/Kg of body weight/day), for a period of 30 days, exhibited a decrease in brain, hippocampus and submandibular salivary gland GSH contents (Ahmed et al. 2022). Moreover, Sprague-Dawley male rats ATZ-exposed via gavage, for 30 days, showed reduction of total antioxidant capacity in a dose-dependent manner, as well as a significant decrease of free GSH level in testicles of these animals (Song et al. 2014).

GSH-depleting agent DEM, likewise, is able to induce a drop in testicular GSH in BALB/c mice. 52 μM of this chemical intraperitoneally injected, during two weeks, leads to a significant reduction of free GSH levels in testicles of these animals (Kalia and Bansal 2008). (Kaur, Kalia, and Bansal 2006) had previously found evidences of relevant diminishment (p < 0.001) of GSH content and elevation of GSSG levels in testicles of this same animal strain daily submitted to DEM intraperitoneal injection, at 8.7 μM, for two weeks.

Regarding Hg, several taxons also have their GSH levels affected in organs and varied tissues. Adult female zebrafish exposed to 15 and 30 μg/L for a period of 30 days, exhibited a reduction of GSH content in ovaries in a dose-dependent manner (Zhang et al. 2016). In male albino Wistar rats, a single dose (5 mg/Kg bw) of a mercury (II) chloride (HgCl2) solution subcutaneously administered, three times a week, for 60 days, was also able to negatively change GSH testicular content (El-Desoky et al. 2013). Nevertheless, the authors also noticed that animals treated with Spirulina platensis (300 mg/Kg bw), by gavage for 10 consecutive days, before mercury (II) chloride administration and continued up to 60 days along with HgCl2, did not suffer changes in GSH levels, emphasizing downstream KE essentiality, once this can be prevented. This GSH reduction is also seen in bird for Hg. Hy-Line Brown laying hens fed with four experimental diets containing gradual levels of mercury at 0.280, 3.325, 9.415 e 27.240 mg/Kg, respectively, for a period of 10 weeks, displayed GSH content considerably decreased in all Hg-treated groups (Ma et al. 2018).

Hence, it is noted that GSH depletion caused by chemicals happens in all stages of live in teleosts, as well as adult mammals and birds, showing that this KER is conserved among these taxa, which is expected, since this antioxidant participates in basic cellular processes in vertebrate organisms. However, the time necessary for this response varies depending on the different stages and among species, as well as it is dependent on the dose/concentration applied. Still, this is not surprising, because toxicokinetics for chemicals obviously differs among taxa and depends on some variables, such as uptake and solubility.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
antioxidant	biflavonone-kolaviron	prevent GSH depletion	Abarikwu, Farombi, and Pant 2011
antioxidant	vitamin E	prevent GSH depletion	Singh, Sandhir, and Kiran 2010

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

GSH depletion depends on the constant conjugation rate of GSH to a xenobiotic, from the initial GSH concentration and its synthesis and degradation rates. Several chemicals that undergo GSH conjugation at high concentrations cause depletion of GSH supplies in the liver and others tissues (D’Souza, Francis, and Andersen 1988; D’Souza and Andersen 1988; Csanády et al. 1996; Mulder and Ouwerkerk-Mahadevan 1997; Fennell and Brown 2001).

In this context, the global kinetic equation for GSH consumption through conjugation to xenobiotics, catalyzed by microsomal glutathione transferase 1 (mGST1), purified from rat liver can be defined by (Spahiu et al. 2017) (figure below.). In this equation, C is the electrophilic substrate, while E represents the enzyme and P serves as a GSH-conjugate. In relation to constants, k₂ is the rate for thiolate anion, k_-2 is the rate for the reverse process of thiolate anion, k₃ is the rate for the chemical step that is essentially irreversible, K_Cis the dissociation constant for electrophilic substrate and K_G is the dissociation constant for GSH (Spahiu et al. 2017).

Moreover, thiolate anion formation (k_obs) can be easily calculated through equations described by (Morgenstern et al. 2001). Kinetic parameters K_M e k_cat values for both electrophiles and GSH can also be determined according to the equations established by (Spahiu et al. 2017).Furthermore, nucleophilic reactivity (N) and electrophilicity (E) parameters of GSH have also been settled to a variety of Michael acceptors (Mayer and Ofial 2019).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Velocity of conjugation, however, depends on the kind of GST involved and on the chemical, as well as the organism in which it takes place. For instance, the ATZ-GSH conjugate formed in GSTs from zebrafish embryos works in a time-dependent manner, although conjugation in the microsomal GST increased linearly by a factor of 23 up to 12 h of incubation time, whereas in the soluble GST the conversion rate increased more slowly and was higher by a factor of 5.8 after 24 h of incubation time than that at start (Wiegand et al. 2001). In rats, the estimated GSH conjugation rate constant with ATZ was 0.53 L/mmol/h, a value comparable to that for other chemicals that are largely conjugated by GSTs, even so less than known depleters such as ethylene dichloride (1.2 L/mmol/h) and allyl chloride (9.0 L/mmol/h). Although ATZ is mostly metabolized by GSH, the model estimated that 50% depletion of GSH is predicted to occur, but only after three daily doses of 500 mg ATZ/Kg (McMullin et al. 2003).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In humans, intrahepatic glutathione concentration is predicted to be the lowest one, due to conjugation to the reactive intermediate NAPQI, at 6 h after 2 g of intravenous (IV) infusion administration of paracetamol and then to recover slowly. In addition, it responds in a time-dependent way. However, concentrations of glutathione were predicted to be markedly and progressively depleted when patients had an initial 2 g dose and then 1 g dose every 6 h (Geenen et al. 2013).

(Hughes, Miller, and Swamidass 2015), for example, constructed a model to predict the GSH reactivity to 1213 molecules and determined the percent depletion of GSH after 15 min incubation with each molecule. In this context, such a model can be easily used for investigation and initial selection of molecules that might impair fertility.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Considering the empirical domain of the evidence, the GSH conjugation leading to GSH depletion is known to occur in all vertebrates animals, but, based on scientific reasoning, it can also occur in eukaryotic organisms in general. It can be measured at any stage of life and in both male and female species.

References

List of the literature that was cited for this KER description. More help

Lu, Shelly C. 2013. “Glutathione Synthesis.” Biochimica et Biophysica Acta 1830 (5): 3143–53.

Aquilano, Katia, Sara Baldelli, and Maria R. Ciriolo. 2014. “Glutathione: New Roles in Redox Signaling for an Old Antioxidant.” Frontiers in Pharmacology 5 (August): 196.

Li, Xianchun. 2009. “Glutathione and Glutathione-S-Transferase in Detoxification Mechanisms.” In General, Applied and Systems Toxicology. Chichester, UK: John Wiley & Sons, Ltd. https://doi.org/10.1002/9780470744307.gat166.

Lushchak, Volodymyr I. 2012. “Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions.” Journal of Amino Acids 2012 (February): 736837.

Gupta, P. K. 2016. “Chapter 8 - Biotransformation.” In Fundamentals of Toxicology, edited by P. K. Gupta, 73–85. Academic Press.

Egaas, E., J. U. Skaare, N. O. Svendsen, M. Sandvik, J. G. Falls, W. C. Dauterman, T. K. Collier, and J. Netland. 1993. “A Comparative Study of Effects of Atrazine on Xenobiotic Metabolizing Enzymes in Fish and Insect, and of the Invitro Phase II Atrazine Metabolism in Some Fish, Insects, Mammals and One Plant Species.” Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology 106 (1): 141–49.

Wiegand, C., E. Krause, C. Steinberg, and S. Pflugmacher. 2001. “Toxicokinetics of Atrazine in Embryos of the Zebrafish (Danio Rerio).” Ecotoxicology and Environmental Safety 49 (3): 199–205.

Elia, A. C., W. T. Waller, and S. J. Norton. 2002. “Biochemical Responses of Bluegill Sunfish (Lepomis Macrochirus, Rafinesque) to Atrazine Induced Oxidative Stress.” Bulletin of Environmental Contamination and Toxicology 68 (6): 809–16.

Abel, Erika L., Shaun M. Opp, Christophe L. M. J. Verlinde, Theo K. Bammler, and David L. Eaton. 2004. “Characterization of Atrazine Biotransformation by Human and Murine Glutathione S-Transferases.” Toxicological Sciences: An Official Journal of the Society of Toxicology 80 (2): 230–38.

McMullin, Tami S., William H. Hanneman, Brian K. Cranmer, John D. Tessari, and Melvin E. Andersen. 2007. “Oral Absorption and Oxidative Metabolism of Atrazine in Rats Evaluated by Physiological Modeling Approaches.” Toxicology 240 (1-2): 1–14.

LeBlanc, André, and Lekha Sleno. 2011. “Atrazine Metabolite Screening in Human Microsomes: Detection of Novel Reactive Metabolites and Glutathione Adducts by LC-MS.” Chemical Research in Toxicology 24 (3): 329–39.

Combes, B., and B. Backof. 1982. “Effect of Diethyl Maleate on the Biliary Excretion Rate of Infused Sulfobromophthalein-Glutathione.” Biochemical Pharmacology 31 (16): 2669–74.

Kubal, G., D. J. Meyer, R. E. Norman, and P. J. Sadler. 1995. “Investigations of Glutathione Conjugation in Vitro by 1H NMR Spectroscopy. Uncatalyzed and Glutathione Transferase-Catalyzed Reactions.” Chemical Research in Toxicology 8 (5): 780–91.

Stricks, W., and I. M. Kolthoff. 1953. “Reactions between Mercuric Mercury and Cysteine and Glutathione. Apparent Dissociation Constants, Heats and Entropies of Formation of Various Forms of Mercuric Mercapto-Cysteine and -Glutathione.” Journal of the American Chemical Society 75 (22): 5673–81.

Valko, M., H. Morris, and M. T. D. Cronin. 2005. “Metals, Toxicity and Oxidative Stress.” Current Medicinal Chemistry 12 (10): 1161–1208.

Wang, Shengchen, Qiaojian Zhang, Shufang Zheng, Menghao Chen, Fuqing Zhao, and Shiwen Xu. 2019. “Atrazine Exposure Triggers Common Carp Neutrophil Apoptosis via the CYP450s/ROS Pathway.” Fish & Shellfish Immunology 84 (January): 551–57.

Santos, Thais G., and Cláudia B. R. Martinez. 2012. “Atrazine Promotes Biochemical Changes and DNA Damage in a Neotropical Fish Species.” Chemosphere 89 (9): 1118–25.

Mela, M., I. C. Guiloski, H. B. Doria, M. A. F. Randi, C. A. de Oliveira Ribeiro, L. Pereira, A. C. Maraschi, V. Prodocimo, C. A. Freire, and H. C. Silva de Assis. 2013. “Effects of the Herbicide Atrazine in Neotropical Catfish (Rhamdia Quelen).” Ecotoxicology and Environmental Safety 93 (July): 13–21.

Adeyemi, Joseph A., Airton da Cunha Martins-Junior, and Fernando Barbosa Jr. 2015. “Teratogenicity, Genotoxicity and Oxidative Stress in Zebrafish Embryos (Danio Rerio) Co-Exposed to Arsenic and Atrazine.” Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP 172-173 (April): 7–12.

Jin, Yuanxiang, Xiangxiang Zhang, Linjun Shu, Lifang Chen, Liwei Sun, Haifeng Qian, Weiping Liu, and Zhengwei Fu. 2010a. “Oxidative Stress Response and Gene Expression with Atrazine Exposure in Adult Female Zebrafish (Danio Rerio).” Chemosphere 78 (7): 846–52.

Toughan, Hosam, Samah R. Khalil, Ashraf Ahmed El-Ghoneimy, Ashraf Awad, and A. Sh Seddek. 2018. “Effect of Dietary Supplementation with Spirulina Platensis on Atrazine-Induced Oxidative Stress- Mediated Hepatic Damage and Inflammation in the Common Carp (Cyprinus Carpio L.).” Ecotoxicology and Environmental Safety 149 (March): 135–42.

Ahmed, Yasmine H., Huda O. AbuBakr, Ismail M. Ahmad, and Zainab Sabry Othman Ahmed. 2022. “Histopathological, Immunohistochemical, And Molecular Alterations In Brain Tissue And Submandibular Salivary Gland Of Atrazine-Induced Toxicity In Male Rats.” Environmental Science and Pollution Research International 29 (20): 30697–711.

Song, Yang, Zhen Chao Jia, Jin Yao Chen, Jun Xiang Hu, and Li Shi Zhang. 2014. “Toxic Effects of Atrazine on Reproductive System of Male Rats.” Biomedical and Environmental Sciences: BES 27 (4): 281–88.

Kalia, Sumiti, and M. P. Bansal. 2008. “Diethyl Maleate-Induced Oxidative Stress Leads to Testicular Germ Cell Apoptosis Involving Bax and Bcl-2.” Journal of Biochemical and Molecular Toxicology 22 (6): 371–81.

Kaur, Parminder, Sumiti Kalia, and Mohinder P. Bansal. 2006. “Effect of Diethyl Maleate Induced Oxidative Stress on Male Reproductive Activity in Mice: Redox Active Enzymes and Transcription Factors Expression.” Molecular and Cellular Biochemistry 291 (1-2): 55–61.

Zhang, Qun-Fang, Ying-Wen Li, Zhi-Hao Liu, and Qi-Liang Chen. 2016. “Reproductive Toxicity of Inorganic Mercury Exposure in Adult Zebrafish: Histological Damage, Oxidative Stress, and Alterations of Sex Hormone and Gene Expression in the Hypothalamic-Pituitary-Gonadal Axis.” Aquatic Toxicology 177 (August): 417–24.

El-Desoky, Gaber E., Samir A. Bashandy, Ibrahim M. Alhazza, Zeid A. Al-Othman, Mourad A. M. Aboul-Soud, and Kareem Yusuf. 2013. “Improvement of Mercuric Chloride-Induced Testis Injuries and Sperm Quality Deteriorations by Spirulina Platensis in Rats.” PloS One 8 (3): e59177.

Ma, Yan, Mingkun Zhu, Liping Miao, Xiaoyun Zhang, Xinyang Dong, and Xiaoting Zou. 2018. “Mercuric Chloride Induced Ovarian Oxidative Stress by Suppressing Nrf2-Keap1 Signal Pathway and Its Downstream Genes in Laying Hens.” Biological Trace Element Research 185 (1): 185–96.

D’Souza, R. W., and M. E. Andersen. 1988. “Physiologically Based Pharmacokinetic Model for Vinylidene Chloride.” Toxicology and Applied Pharmacology 95 (2): 230–40.

D’Souza, R. W., W. R. Francis, and M. E. Andersen. 1988. “Physiological Model for Tissue Glutathione Depletion and Increased Resynthesis after Ethylene Dichloride Exposure.” The Journal of Pharmacology and Experimental Therapeutics 245 (2): 563–68.

Mulder, G. J., and S. Ouwerkerk-Mahadevan. 1997. “Modulation of Glutathione Conjugation in Vivo: How to Decrease Glutathione Conjugation in Vivo or in Intact Cellular Systems in Vitro.” Chemico-Biological Interactions 105 (1): 17–34.

Fennell, T. R., and C. D. Brown. 2001. “A Physiologically Based Pharmacokinetic Model for Ethylene Oxide in Mouse, Rat, and Human.” Toxicology and Applied Pharmacology 173 (3): 161–75.

Spahiu, Linda, Johan Ålander, Astrid Ottosson-Wadlund, Richard Svensson, Carina Lehmer, Richard N. Armstrong, and Ralf Morgenstern. 2017a. “Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation.” Biochemistry 56 (24): 3089–98.

Csanády, G. A., P. E. Kreuzer, C. Baur, and J. G. Filser. 1996. “A Physiological Toxicokinetic Model for 1,3-Butadiene in Rodents and Man: Blood Concentrations of 1,3-Butadiene, Its Metabolically Formed Epoxides, and of Haemoglobin Adducts--Relevance of Glutathione Depletion.” Toxicology 113 (1-3): 300–305.

Morgenstern, R., R. Svensson, B. A. Bernat, and R. N. Armstrong. 2001. “Kinetic Analysis of the Slow Ionization of Glutathione by Microsomal Glutathione Transferase MGST1.” Biochemistry 40 (11): 3378–84.

Mayer, Robert J., and Armin R. Ofial. 2019. “Nucleophilicity of Glutathione: A Link to Michael Acceptor Reactivities.” Angewandte Chemie 58 (49): 17704–8.

McMullin, Tami, Jill Brzezicki, Brian Cranmer, John Tessari, and Melvin Andersen. 2003. “Pharmacokinetic Modeling of Disposition and Time-Course Studies With [ 14 C]Atrazine.” Journal of Toxicology and Environmental Health. Part A 66 (10): 941–64.

Geenen, Suzanne, James W. T. Yates, J. Gerry Kenna, Frederic Y. Bois, Ian D. Wilson, and Hans V. Westerhoff. 2013. “Multiscale Modelling Approach Combining a Kinetic Model of Glutathione Metabolism with PBPK Models of Paracetamol and the Potential Glutathione-Depletion Biomarkers Ophthalmic Acid and 5-Oxoproline in Humans and Rats.” Integrative Biology: Quantitative Biosciences from Nano to Macro 5 (6): 877–88.

Hughes, Tyler B., Grover P. Miller, and S. Joshua Swamidass. 2015. “Site of Reactivity Models Predict Molecular Reactivity of Diverse Chemicals with Glutathione.” Chemical Research in Toxicology 28 (4): 797–809.

Abarikwu, S. O., E. O. Farombi, and A. B. Pant. 2011. “Biflavanone-Kolaviron Protects Human Dopaminergic SH-SY5Y Cells against Atrazine Induced Toxic Insult.” Toxicology in Vitro: An International Journal Published in Association with BIBRA 25 (4): 848–58.

Singh, Mohan, Rajat Sandhir, and Ravi Kiran. 2010. “Oxidative Stress Induced by Atrazine in Rat Erythrocytes: Mitigating Effect of Vitamin E.” Toxicology Mechanisms and Methods 20 (3): 119–26.