Molecular Mechanisms of Apoptosis Induced by Cytotoxic Chemicals
- 1 January 2000
- journal article
- review article
- Published by Taylor & Francis in Critical Reviews in Toxicology
- Vol. 30 (5) , 609-627
- https://doi.org/10.1080/10408440008951122
Abstract
The purpose of this review article is to discuss established molecular mechanisms of apoptosis and their relevance to cell death induced by environmental toxicants. Apoptosis is a highly regulated form of cell death distinguished by the activation of a family of cysteine-aspartate proteases (caspases) that cleave various proteins resulting in morphological and biochemical changes characteristic of this form of cell death. Abundant evidence supports a role for mitochondria in regulating apoptosis. Specifically, it seems that a number of death stimuli target these organelles and stimulate, by an unknown mechanism, the release of several proteins, including cytochrome c. Once released into the cytosol, cytochrome c binds to its adaptor molecule, Apaf-1, which oligomerizes and then activates pro-caspase-9. Caspase-9 can signal downstream and activate pro-caspase-3 and -7. The release of cytochrome c can be influenced by different Bcl-2 family member proteins, including, but not limited to, Bax, Bid, Bcl-2, and Bcl-X(L). Bax and Bid potentiate cytochrome c release, whereas Bcl-2 and Bcl-X(L) antagonize this event. Although toxicologists have traditionally associated cell death with necrosis, emerging evidence suggests that different types of environmental contaminants exert their toxicity, at least in part, by triggering apoptosis. The mechanism responsible for eliciting the pro-apoptotic effect of a given chemical is often unknown, although in many instances mitochondria appear to be key participants. This review describes our current understanding of the role of apoptosis in environmental toxicant-induced cell death, using dioxin, metals (cadmium and methylmercury), organotin compounds, dithiocarbamates, and benzene as specific examples. Finally, we conclude with a critical discussion of the current knowledge in this area and provide recommendations for future directions.Keywords
This publication has 132 references indexed in Scilit:
- Cytosolic Nuclease Activated by Caspase-3 and Inhibited by DFF-45Biochemical and Biophysical Research Communications, 1998
- Evidence for the Induction of Apoptosis in Thymocytes by 2,3,7,8-Tetrachlorodibenzo-p-dioxinin VivoToxicology and Applied Pharmacology, 1997
- Reactive Oxygen Species Participate in Peroxynitrite-Induced Apoptosis in HL-60 CellsBiochemical and Biophysical Research Communications, 1997
- Methylmercury Induces Apoptosis of Rat Cerebellar Neurons in Primary CultureBiochemical and Biophysical Research Communications, 1994
- Bcl‐2 protects from oxidative damage and apoptotic cell death without interfering with activation of NF‐κB by TNFFEBS Letters, 1994
- Rapid Cytoskeleton Modification in Thymocytes Induced by the Immunotoxicant TributyltinToxicology and Applied Pharmacology, 1994
- Dexamethasone, β-Estradiol, and 2,3,7,8-Tetrachlorodibenzo-p-dioxin Elicit Thymic Atrophy through Different Cellular TargetsToxicology and Applied Pharmacology, 1994
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) kills glucocorticoid-sensitive thymocytes invivoBiochemical and Biophysical Research Communications, 1989
- Antioxidant effect of diethyldithiocarbamate on microsomal lipid peroxidation assessed by low-level chemiluminescence and alkane productionFEBS Letters, 1983
- Studies of cadmium-thionein induced nephropathy: Time course of cadmium-thionein uptake and degradationChemico-Biological Interactions, 1983