Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens [22]

Janardan K Reddy*, D. L. Azarnoff, C. E. Hignite

*Corresponding author for this work

Research output: Contribution to journalLetter

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Abstract

Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate) 1, are now available for the treatment of hyperlipidaemias 2,3 and others are in the process of preclinical or clinical evaluation4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US2, as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats6-8, mice 7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species6-8. These ubiquitous cytoplasmic organelles9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase11 as well as enzymes involved in the β-oxidation of long-chain fatty acids12. The activities of these enzymes in liver are elevated in association with peroxisome proliferation8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CSb mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]- propionic acid)14-16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid)17, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia8. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5% in the diet18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β- hydroxyethyl)-acetamide])20and tibric acid(2-chloro-5-(3,5- dimethylpiperidinosulphonyl)benzoic acid)8, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CSb mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.

Original languageEnglish (US)
Pages (from-to)397-398
Number of pages2
JournalNature
Volume283
Issue number5745
DOIs
StatePublished - Dec 1 1980

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Peroxisome Proliferators
Carcinogens
Clofibrate
Peroxisomes
Liver
Hepatomegaly
Inbred F344 Rats
Clofibric Acid
Pharmaceutical Preparations
Hypolipidemic Agents
Benzoic Acid
Carnitine
Enzymes
Hyperlipidemias
Cricetinae
Catalase
Hydrogen Peroxide
Hepatocellular Carcinoma
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Reddy, Janardan K ; Azarnoff, D. L. ; Hignite, C. E. / Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens [22]. In: Nature. 1980 ; Vol. 283, No. 5745. pp. 397-398.
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abstract = "Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate) 1, are now available for the treatment of hyperlipidaemias 2,3 and others are in the process of preclinical or clinical evaluation4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US2, as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats6-8, mice 7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species6-8. These ubiquitous cytoplasmic organelles9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase11 as well as enzymes involved in the β-oxidation of long-chain fatty acids12. The activities of these enzymes in liver are elevated in association with peroxisome proliferation8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CSb mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]- propionic acid)14-16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid)17, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia8. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5{\%} in the diet18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β- hydroxyethyl)-acetamide])20and tibric acid(2-chloro-5-(3,5- dimethylpiperidinosulphonyl)benzoic acid)8, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CSb mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.",
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Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens [22]. / Reddy, Janardan K; Azarnoff, D. L.; Hignite, C. E.

In: Nature, Vol. 283, No. 5745, 01.12.1980, p. 397-398.

Research output: Contribution to journalLetter

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T1 - Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens [22]

AU - Reddy, Janardan K

AU - Azarnoff, D. L.

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PY - 1980/12/1

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N2 - Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate) 1, are now available for the treatment of hyperlipidaemias 2,3 and others are in the process of preclinical or clinical evaluation4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US2, as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats6-8, mice 7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species6-8. These ubiquitous cytoplasmic organelles9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase11 as well as enzymes involved in the β-oxidation of long-chain fatty acids12. The activities of these enzymes in liver are elevated in association with peroxisome proliferation8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CSb mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]- propionic acid)14-16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid)17, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia8. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5% in the diet18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β- hydroxyethyl)-acetamide])20and tibric acid(2-chloro-5-(3,5- dimethylpiperidinosulphonyl)benzoic acid)8, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CSb mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.

AB - Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate) 1, are now available for the treatment of hyperlipidaemias 2,3 and others are in the process of preclinical or clinical evaluation4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US2, as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats6-8, mice 7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species6-8. These ubiquitous cytoplasmic organelles9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase11 as well as enzymes involved in the β-oxidation of long-chain fatty acids12. The activities of these enzymes in liver are elevated in association with peroxisome proliferation8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CSb mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]- propionic acid)14-16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid)17, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia8. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5% in the diet18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β- hydroxyethyl)-acetamide])20and tibric acid(2-chloro-5-(3,5- dimethylpiperidinosulphonyl)benzoic acid)8, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CSb mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.

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