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Toxicology, Cellular Stress & Stress Response

The understanding of drug–body interactions is crucial to drug development. Drug absorption, distribution, metabolism and excretion (ADME) is critical in all phases of drug development programs, providing key insights into how a drug will ultimately be treated or accepted by the body. In the late 1980s to the mid-1990s, 40% of all drug failures in clinical trials were due to unfavorable toxicology and ADME profiles. By developing and using new focused genomic tools, researchers are better prepared to test compounds to protect human health and the environment. 

Several hundred key genes in at least 13 different biological pathways can be activated in response to toxic drugs. Profiling the expression of these genes in human cell lines (such as hepatocytes) or organs (especially livers) of mice or rats treated with candidate drugs can help indicate which toxicological responses have been induced. Understanding these mechanisms can then guide chemical modifications to avoid the observed toxic responses rather than completely dismissing a drug class otherwise effective at preventing or treating the target disease phenotype. The toxic response pathways can be independent or interrelated. For example, inhibition of β-oxidation leads to steatosis, and uncoupling mitochondrial energy metabolism leads to apoptosis and necrosis. Drugs affecting reactive oxygen species metabolism or cellular redox status cause oxidative stress and induce antioxidant responses. These and other reactive drugs also directly damage DNA or inhibit its repair, thereby activating DNA damage signaling and DNA repair pathways. More extreme conditions of prolonged exposure or excess damage to DNA, cells or tissues may induce apoptosis and necrosis. Interference with protein synthesis causes endoplasmic reticulum stress and activates the unfolded protein response, resulting in up-regulation of heat shock protein and chaperone gene expression. Increased expression of the cytochrome P450 and other phase I drug metabolism enzymes occurs when drugs inhibit or overwhelm their chemical modification activities. More severe and complex phenomena result when drugs inhibit fatty acid and lipid metabolism (β-oxidation), including the lipid storage disorders of steatosis, cholestasis and phospholipidosis. Toxic responses to drugs in immune system cells bring about immunotoxicity and immunosuppression. 

 

FAQs About Toxicology, Cellular Stress & Stress Response

What defines toxicology and its relevance to cellular stress mechanisms?
Toxicology explores the harmful effects of chemical, physical, and biological agents on living organisms and the environment. It studies the detection, mechanisms, and treatments of poisoning and helps to understand how toxicity induces cellular stress, disrupts cellular function, and potentially leads to chronic diseases.
How do external and internal stressors trigger cellular stress responses?
When faced with external stressors such as heavy metals, allergens, drugs or toxins, pollutants, pesticides, or insecticides and internal stressors like free radicals, DNA damage, and hypoxia that interfere with cellular homeostasis, cells respond by triggering a series of complex signaling pathways involved in many cellular activities, including cell repair and cell death (1, 2). These responses help reestablish cellular homeostasis and help cells adapt to the new environment (2).
How do cellular stress response pathways mitigate the effects of toxins?
Cellular stress response pathways mitigate toxin effects by activating cellular mechanisms that help the cells detoxify, repair damage, survive, and remove damaged cells from the body. These mechanisms include antioxidant responses to counteract oxidative injury, DNA repair systems to reverse toxin-induced damage that alters DNA structure, and the unfolded protein response to help restore cellular homeostasis by stopping translation of mRNA to protein, eliminating misfolded proteins, and activating genes that prevent additional misfolding (3). Others like the xenobiotic pathways work by enzymatically modifying harmful chemicals and a primary hypoxia response entails modifying gene transcription to promote cell survival (4).
Why are cellular stress response pathways critical for preventing disease and maintaining health?
Stress response pathways are cellular mechanisms for resisting the effects of environmental stressors and internal disturbances to maintain cellular integrity, function, survival, and adaptability. Without these pathways, cells become damaged, stop functioning, and eventually die, which can disrupt the proper functioning of processes required for an organism's survival and initiate pathogenesis. Hence these pathways prevent the onset and progression of diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases.
What mechanisms do cells use to defend against oxidative damage?

Cells use antioxidant defense systems that include antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and molecules, such as glutathione, bilirubin, vitamins E and C, uric acid and creatine to defend against oxidative damage (5).

The antioxidants working in the defense systems act at four levels. The first line is the preventive antioxidants that prevent free radicals from forming. The second defense level is the antioxidants that find and suppress the active radicals. The third line of defense is the antioxidants that repair damage caused by free radicals. Lastly is adaptation, which occurs when the signal for free radical production induces the appropriate antioxidant to form and move to its needed location (6).

How does xenobiotic metabolism contribute to detoxification?
Xenobiotics are chemical substances foreign to animal life, including plant constituents, drugs, pesticides, industrial chemicals, cosmetics, flavorings, fragrances, food additives, and environmental pollutants (7). Xenobiotic metabolism is a critical process in detoxification, involving enzymes including members of the cytochrome P450 family that convert xenobiotics to more water-soluble forms that can be excreted (8). Efficient xenobiotic metabolism prevents the accumulation of harmful substances in the body, which can help protect against many diseases.
What is the significance of SAPK/JNK signaling in cellular responses to stress?
The SAPK/JNK signaling pathway is activated in response to extracellular stressors, including UV radiation, bacterial and viral infection, and heat shock (9). This pathway culminates in altered transcription that promotes cell survival, proliferation, inflammation, migration, and metabolic reprogramming (10). Dysregulated SAPK/JNK signaling is implicated in cancer, chronic inflammation, neurological diseases, and other pathologies, making it a significant focus in stress pharmacology.
How does the unfolded protein response (UPR) function under cellular stress?
The unfolded protein response (UPR) is a cellular stress response activated when unfolded or misfolded proteins build up in the endoplasmic reticulum due to stressors like hypoxia, viral infection, and altered glycosylation(11). This buildup of misfolded or unfolded proteins is toxic to cells and can impede cellular function (12). The unfolded protein response restores balance in the number of unfolded or misfolded proteins in the cell by reducing how many proteins need folding, improving the endoplasmic reticulum’s folding capacity, and eliminating unfolded proteins that fold more slowly (12).
What role does mitochondrial dysfunction play in disease pathology?

Healthy mitochondria are critical for producing cellular energy and ensuring cellular functioning and survival. Mitochondrial dysfunction may occur due to a failure to maintain the electrical and chemical transmembrane potential of the mitochondrial membrane, changes in electron transport chain functioning, or reduced release of essential metabolites into mitochondria. These changes reduce the efficiency of oxidative phosphorylation and adenosine-5′-triphosphate (ATP) production (13).

Hence, mitochondria are an attractive target for treating, diagnosing, and preventing many chronic diseases, including metabolic disorders, neurobehavioral and psychiatric diseases, cancer, cardiovascular diseases, and neurodegenerative diseases (14).

What are the consequences of unresolved endoplasmic reticulum stress?
Endoplasmic reticulum stress is characterized by endoplasmic reticulum distension and disruption of endoplasmic reticulum homeostasis (15). Here the membrane is disrupted, leading to the accumulation of misfolded and unfolded proteins in the endoplasmic reticulum stress. Left unresolved, it can lead to cellular dysfunction, inflammation, and death (15). Prolonged or severe endoplasmic reticulum stress is implicated in the development of diseases, including diabetes, neurodegenerative diseases, renal diseases, and cardiovascular diseases. Pathways involved in endoplasmic reticulum stress, including IRE1, PERK, and ATF6, are promising targets in developing treatments for these diseases (11).
How are oxidative stress, mitochondrial function and protein folding interconnected in cellular stress responses?
Oxidative stress, mitochondrial dysfunction, and impaired protein folding are strongly linked processes that can create a cycle of cellular damage and dysfunction. For example, mitochondrial dysfunction may result in excessive reactive oxygen species (ROS) production that can overburden the endoplasmic reticulum’s protein folding capacity and cause oxidative stress, further contributing to mitochondrial homeostasis impairments. Understanding the interconnectedness of cellular stress responses is crucial for developing improved interventions for many chronic diseases (16).

References and further reading

  1. Sharifi-Rad M, Anil Kumar NV, Zucca P, et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Front Physiol. 2020;11:694. Published 2020 Jul 2.
  2. Poljšak B, Milisav I. Clinical implications of cellular stress responses. Bosn J Basic Med Sci. 2012;12(2):122-126.
  3. Liu J, Bi K, Yang R, Li H, Nikitaki Z, Chang L. Role of DNA damage and repair in radiation cancer therapy: a current update and a look to the future. Int J Radiat Biol. 2020;96(11):1329-1338.
  4. D'Alessandro S, Magnavacca A, Perego F, et al. Effect of Hypoxia on Gene Expression in Cell Populations Involved in Wound Healing. Biomed Res Int. 2019;2019:2626374. Published 2019 Aug 22.
  5. ScienceDirect https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress#:~:text=Oxidative%20stress%20is%20suppressed%20by,C%2C%20uric%20acid%20and%20creatine (Accessed May 24, 2024)
  6. Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010;4(8):118-126.
  7. Patterson AD, Gonzalez FJ, Idle JR. Xenobiotic metabolism: a view through the metabolometer. Chem Res Toxicol. 2010;23(5):851-860.
  8. Manikandan P, Nagini S. Cytochrome P450 Structure, Function and Clinical Significance: A Review. Curr Drug Targets. 2018;19(1):38-54.
  9. Hammouda MB, Ford AE, Liu Y, Zhang JY. The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer. Cells. 2020;9(4):857. Published 2020 Apr 2.
  10. Yan H, He L, Lv D, Yang J, Yuan Z. The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review. Biomolecules. 2024;14(2):243. Published 2024 Feb 19.
  11. Read A, Schröder M. The Unfolded Protein Response: An Overview. Biology (Basel). 2021;10(5):384. Published 2021 Apr 29.
  12. Haeri M, Knox BE. Endoplasmic Reticulum Stress and Unfolded Protein Response Pathways: Potential for Treating Age-related Retinal Degeneration. J Ophthalmic Vis Res. 2012;7(1):45-59.
  13. Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. Integr Med (Encinitas). 2014;13(4):35-43.
  14. Khan T, Waseem R, Zehra Z, et al. Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches. Pharmaceutics. 2022;14(12):2657. Published 2022 Nov 30.
  15. Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):352. Published 2023 Sep 15.
  16. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8(21):2003-2014.

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