Peroxisomes chemicals that induce proliferation

A peroxisome proliferator is a chemical that induces peroxisome proliferation in rodent liver and other tissues and includes a wide range of chemicals such as certain herbicides, plasticizers, drugs, and natural products [38,39], The peroxisomes contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism and activation of the peroxisome proliferator-activated receptor alpha (PPARa), is considered a key event in peroxisome proliferation in rodent hepatocytes [39], A number of studies have identified... 

Peroxisomal proliferators chemicals that change the number and characteristics of peroxisomes (intracellular organelles which carry out oxidation of fatty acids). These chemicals also may cause liver cancer and induce a number of enzymes. 

Peroxisomes are subcellular organelles found in the cytoplasm of mammalian cells that carry out important metabolic functions (de Duve 1996 Hashimoto 1996 Mannaerts and van Veldhoven 1996). Under a variety of altered physiological and metabolic states, peroxisomes are known to proliferate, most notably with increased concentrations of unsaturated and polyunsaturated fatty acids. Interest in the toxicology community was piqued when peroxisome proliferation was noted in rodent hepatocytes in response to the administration of certain xenobiotics (e.g., Hess et al. 1965 Reddy and Chu 1996 Reddy and Rao 1977). Based on the association between exposure and peroxisome proliferation, the chemical and pharmaceutical agents that induce this response have been collectively referred to as peroxisome proliferators. ... 

PPARa activators are a unique class of chemical carcinogens that induce peroxisome proliferation and increase the incidence of Uver tumors in rats and/or mice. These include several hypohpidemic drugs (e.g., WY-14,643, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate) and environmentally relevant compounds such as phthalates or their metabolites (e.g., di-(2-ethylhexyl) phthalate (DEHP), di-(2-ethylhexyl) adipate (DEHA), diisononyl phthalate (DINP), or 2-ethylhexanol (2-EH)), pesticides (e.g., 2,4-dichlorophenoxyacetic acid, diclofopmethyl, haloxyfop, lactofen, oxidiazon), solvents (e.g., perchloroethylene, trichloroethylene), and other industrial chemicals (e.g., HCFC-123, PFOA) (smnmarized in Klaunig etal. (2003)). 

Several important characteristics of chemicals which induce the proliferation of peroxisomes in animals is that they display clear thresholds and species-dependency in the induction of proliferation (see review by Stott (73) and references contained therein). In rodent bioassays, no tumorigenic response is observed at nonproliferating dose levels and higher mammalian species are quite refractory to the proliferative effects of these chemicals. Indeed primates, including humans, appear to be so refractory to the chemically-induced proliferation of peroxisomes that this response, and any carcinogenic hazard associated with it, is generally considered to represent a rodent specific phenomenon. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Ethanol and a number of other chemicals, including acetone and certain imidazoles, induce CYP2E1. Piperonyl butoxide, isosafrole, and other methylenedioxyphenyl compounds are known to induce CYP1A2 by a non-Ah receptor-dependent mechanism. Peroxisome proliferators, including the drug, clofibrate, and the herbicide synergist tridiphane induce a CYP4A isozyme that catalyzes the -oxidation of lauric acid. 

Inducers of cytochromes P450 IV that are involved in peroxisome proliferation, which brings about carcinogenicity in rodents, are quite difficult to identify using COMPACT. However, because these chemicals usually possess an acidic function, or an isostere, combined with at least one aromatic ring in a specific orientation relative to the acid moiety, it is possible to predict potential peroxisome proliferators by structural analogy with known inducers such as... 

The toxieity of triehloroethylene is dependent upon metabolism and induction of cytochrome P450. Triehloroethylene is metabolized through chloral hydrate to compounds including trichloroacetic acid and dichloroacetic acid which alter intercellular communication, induce peroxisome proliferation and may promote tumor production. Significant variability in trichloroethylene metabolism in 23 human haptic microsomal samples was reported by Lipscomb et al. It was also demonstrated that the trichloroethylene metabolism is dependent on enzymatic activities of the cytochrome system, and they conclude that their data indicates that humans are not uniform in their capacity for CPY dependent metabolism of trichloroethylene and increased activity may increase susceptibility to trichloroethylene induced toxicity in humans. These observations are compatible with the variability reaction which is depending on nutritional factors, enzyme induction factors, hormonal factors and interaction with other environmental chemicals, prescription medications and general health conditions, and explains the variable reports as far as trichloroethylene and level of liver toxicity in the various individuals studied. 

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