Hepatocarcinogenic peroxisome

The SAR of peroxisome proliferators has been reviewed ((Bentley et al. 1993 Lai 2004 Lake and Lewis 1993 Woo and Lai 2003)). Figure 20.1 shows the chemical structures for a variety of hepatocarcinogenic peroxisome proliferatiors. However, at first glance the chemical structures appear to be diverse. From the mechanistic point of view, there are two common features (a) firtually aU the... 

On the basis of these differences in species response it was concluded that phthalates do not pose a significant health hazard to humans. This view is home out by the EU Commission decision of July 25, 1990 which states that DEHP shall not be classified or labeled as a carcinogenic or an irritant substance (42). This has been reaffirmed in a comprehensive review (43) which concludes that "peroxisome proliferators constitute a discrete class of nongenotoxic rodent hepatocarcinogens and that the relevance of thek hepatocarcinogenic effects for human hazard assessment is considered to be negligible."... 

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... 

Caitley, R. C. et al. (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans Regulatory Toxicology and Pharmacology. 27, 47-60. 

Lake, B.G (1995b) Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drags and chemicals. Ann. Rev. Pharmacol. Toxicol., 35, 483-507... 

Cattley, R.C. Glover, S.E. (1993) Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators relationship to carcinogenesis and nuclear localization. Carcinogenesis, 14, 2495-2499 Cattley, R.C., Conway, J.G Popp, J.A. (1987) Association of persistent proliferation and oxidative injury with hepatocarcinogenicity in female F-344 rats fed di(2-ethylhexyl)-phthalate for 2 years. Cancer Lett., 38, 15-22... 

Hsu, M.H., Palmer, C.N., Griffin, K.J. Johnson, E.F. (1995) A single amino acid change in the mouse peroxisome proliferator-activated receptor alpha alters transcriptional responses to peroxisome proliferators. Mol. Pharmacol., 48, 559-567 Huber, W.W., Grasl-Kraupp, B. Schulte-Hermann, R. (1996) Hepatocarcinogenic potential of di-(2-ethylhexyl) phthalate in rodents and its implications on human risk. Grit. Rev. Toxicol., 26, 365-481... 

Lake, B.G (1995b) Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drags and chemicals. Ann. Rev. Pharmacol. Toxicol., 35, 483-507 Lake, B.G, Gangolli, S.D., Grasso, P. Lloyd, A.G (1975) Studies on the hepatic effects of orally administered di-(2-ethylhexyl) phthalate in the rat. Toxicol, appl. Pharmacol., 32, 355-367... 

Mallette, F.S. von Haam, E. (1952) Studies on the toxicity and skin effects of compounds used in the mbber and plastics indnstiies. II. Plasticizers. Arc/r. ind. Hyg. occup. Med., 6, 231-236 Maloney, E.K. Waxman, D.J. (1999) iran -Activation of PPARa and PPARyby stmcturally diverse enviromnental chemicals. Toxicol, appl. Pharmacol, 161, 209-218 Marsman, D.S., Cattley, R.C., Conway, J.G Popp, J.A. (1988) Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res., 48, 6739-6744... 

Popp, J.A., Garvey, L.K., Hamm, T.E., Jr Swenberg, J.A. (1985) Lack of hepatic promotional activity by the peroxisomal proliferating hepatocarcinogen di(2-ethylhexyl)phthalate. Carcinogenesis, 6,141-144 Preston, M.R. Al-Omran, L.A. (1989) Phthalate ester speciation in estuarine water, suspended particulates and sediments. Environ. Pollut., 62, 183-193 Priston, R.A.J. Dean, B.J. (1985) Tests for the induction of chromosome aberrations, polyploidy and sister-chromatic exchanges in rat liver (RL4) cells. Prog. Mutat. Res., 5, 387-395... 

Reddy, J.K., Moody, D.E., Azamoff, D.L. Rao, M.S. (1976) Di-(2-ethylhexyl)phthalate an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rat and mice. Life Sci., 18, 941-945 Reddy, J.K., Reddy, M.K., Usman, M L, Lalwani, N.D. Rao, M S. (1986) Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drag. Environ. Health Perspect., 65, 317-327 Rexroat, M.A. Probst, GS. (1985) Mutation tests with Salmonella using the plate-incorporation assay. Prog. Mutat. Res., 5, 201-212 Rhodes, C., Orton, T.C., Pratt, I.S., Batten, P.L., Bratt, H., Jackson, S.J. Elcombe, C.R. (1986) Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets extrapolation of effects in rodents to man. Environ. Health Perspect., 65, 299-307... 

Cattley, R.C., DeLuca, J., Elcombe, C., Eenner-Crisp, R, Lake, B.G, Marsman, D.S., Pastoor, T.A., Popp, J.A., Robinson, D.E., Schwetz, B., Tugwood, J. Wahli, W. (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans Regul. Toxicol. Pharmacol., 27, 47-60... 

PPAR a receptor, gap junctional intercellular communication, and replicative DNA synthesis (Isenberg et al. 2000, 2001 Smith et al. 2000). Two major mechanisms have been proposed to account for peroxisome proliferator-induced hepatocarcinogenicity in rodents induction of sustained oxidative stress and enhanced cell proliferation and promotion. Suppression of hepatocellular apoptosis has also been suggested to play a role. 

Cattley RC, Conway JG, Popp JA. 1987. Association of persistent peroxisome proliferation and oxidative injury with hepatocarcinogenicity in female F-344 rats fed di(2-cthylhcxyl)phthalate for 2 years. Cancer Lett 38 15 -21. 

Conway JG, T omaszewski KE, Olson MJ, et al. 1989. Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-cthylhcxyl)phthalatc and Wy-14,643. Carcinogenesis 10 513-519. 

HayashiF, Motoki Y, Tamura H, et al. 1998. Induction of hepatic poly(ADP-ribose) polymerase by peroxisome proliferators, non-genotoxic hepatocarcinogens. Cancer Lett 127 1-7. 

Lake BG. 1995. Mechanisms of hepatocarcinogenicity of peroxisome-pro liferating drugs and chemicals. Annu Rev Pharmacol Toxicol 35 483-507. 

Marsman DS, Cattley RC, Conway JG, et al. 1988. Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643)in rats. Cancer Res 48 6739-6744. 

Orner, G.A., C. Mathews, J.D. Hendricks, H.M. Carpenter, G.S. Bailey and D.E. Williams. Dehydroepiandrosterone is a complete hepatocarcinogen and potent tumor promoter in the absence of peroxisome proliferation in rainbow trout. Carcinogenesis 16 2893-2898, 1995. 

Elcock, F. J., Chipman, J. K., and Roberts, R. A. (1998). The rodent nongenotoxic hepatocarcinogen and peroxisome proliferator nafenopin inhibits intercellular communication in rat but not guinea-pig hepatocytes, perturbing S-phase but not apoptosis. Arch Toxicol 72, 439 44. 

Marsman, D. S., Goldsworthy, T. L., and Popp, J. A. (1992). Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. Carcinogenesis 13, 1011-1017. 

Rolfe, M., James, N. H., and Roberts, R. A. (1997). Tumour necrosis factor al[4ia (TNF al[4ia) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes a mediator of the hepatocarcinogenicity of peroxisome proUferators Carcinogenesis 18, 2277-2280. 

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