Mecanismos De Toxicidad En Ingles

CHAPTER 3

MECHANISMS OF TOXICITY
Zoltán Gregus and Curtis D. Klaassen
STEP 1—DELIVERY: FROM THE SITE OF EXPOSURE TO THE TARGET Absorption versus Presystemic Elimination Absorption Presystemic Elimination Distribution to and Away from the Target Mechanisms Facilitating Distribution to a Target Mechanisms Opposing Distribution to a Target Excretion versus Reabsorption Excretion ReabsorptionToxication versus Detoxication Toxication Detoxication STEP 2—REACTION OF THE ULTIMATE TOXICANT WITH THE TARGET MOLECULE Attributes of Target Molecules Types of Reactions Noncovalent Binding Covalent Binding Hydrogen Abstraction Electron Transfer Enzymatic Reactions Effects of Toxicants on Target Molecules Dysfunction of Target Molecules Destruction of Target Molecules Neoantigen Formation ToxicityNot Initiated by Reaction with Target Molecules STEP 3—CELLULAR DYSFUNCTION AND RESULTANT TOXICITIES Toxicant-Induced Cellular Dysregulation Dysregulation of Gene Expression Dysregulation of Ongoing Cellular Activity Toxic Alteration of Cellular Maintenance Impairment of Internal Cellular Maintenance: Mechanisms of Toxic Cell Death Impairment of External Cellular Maintenance STEP 4—REPAIR ORDYSREPAIR Molecular Repair Repair of Proteins Repair of Lipids Repair of DNA Cellular Repair: A Strategy in Peripheral Neurons Tissue Repair Apoptosis: An Active Deletion of Damaged Cells Proliferation: Regeneration of Tissue Side Reactions to Tissue Injury When Repair Fails Toxicity Resulting from Dysrepair Tissue Necrosis Fibrosis Carcinogenesis CONCLUSIONS

Depending primarily on the degree androute of exposure, chemicals may adversely affect the function and/or structure of living organisms. The qualitative and quantitative characterization of these harmful or toxic effects is essential for an evaluation of the potential hazard posed by a particular chemical. It is also valuable to understand the mechanisms responsible for the manifestation of toxicity—that is, how a toxicant enters anorganism, how it interacts with target molecules, and how the organism deals with the insult. An understanding of the mechanisms of toxicity is of both practical and theoretical importance. Such information provides a rational basis for interpreting descriptive toxicity data, estimating the probability that a chemical will cause harmful effects, establishing procedures to prevent or antagonize thetoxic effects, designing drugs and industrial chemicals that are less hazardous, and developing pesticides that are more selectively toxic for their target organisms. Elucidation of the mechanisms of chemical toxicity has led to a better understanding of fundamental physiologic and biochemical processes ranging from neurotransmission (e.g., curare-type arrow poisons) to deoxyribonucleic acid (DNA)repair 35

(e.g., alkylating agents). Pathologic conditions such as cancer and Parkinson’s disease are better understood because of studies on the mechanism of toxicity of chemical carcinogens and 1,2,3,6tetrahydro-1-methyl-4-phenylpyridine (MPTP), respectively. Continued research on mechanisms of toxicity will undoubtedly continue to provide such insights. This chapter reviews the cellularmechanisms that contribute to the manifestation of toxicities. Although such mechanisms are dealt with elsewhere in this volume, they are discussed in detail in this chapter in an integrated and comprehensive manner. We provide an overview of the mechanisms of chemical toxicity by relating a series of events that begins with exposure, involves a multitude of interactions between the invading toxicantand the organism, and culminates in a toxic effect. This chapter focuses on mechanisms that have been identified definitively or tentatively in humans or animals. As a result of the huge number of potential toxicants and the multitude of biological structures and processes that can be impaired, there are a tremendous number of possible toxic effects.

36

UNIT 1 GENERAL PRINCIPLES OF...