Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-α-p-chlorophenoxyisobutyrate (clofibrate) in rats

Reddy, J. K.; Qureshi, Saeed A.

doi:10.1038/bjc.1979.203

Cited by 140 publications

(51 citation statements)

References 24 publications

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“…Clofibrate is a drug with inconclusive or conflicting evidence of carcinogenicity in relation to hepatic, pancreatic and gastrointestinal malignancies (Hoover & Fraumeni, 1981;Reddy & Qureshi, 1979;Cohen & Grasso, 1981). The hepatic peroxisome proliferation effect is related to carcinogenicity in rats (Reddy & Krishnakantha, 1975), However, results reported here are consistent with the possibility that CPIB-induced tumour facilitation in rodents is not so much a function of if carcinogenic/tumour promotional activity as of its properties as an immunological depressant.…”

Section: Resultssupporting

confidence: 80%

Effect of clofibrate on the growth-kinetics of the murine P 1798(sc) lymphoma

Ubeira¹,

Prado²,

Puentes³

et al. 1983

Br J Cancer

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Summary Clofibrate (CPIB) is a drug applied as an antilipidaemic agent in mammals. In this work we have tested its efficacy in vivo on the growth kinetics of P 1798(sc) lymphoma transplanted to recipient (BALB/c x AKR)F1 mice. Our results show a facilitation of the tumour growth rate in treated recipients. This fact may be related to an effect of the agent on the recipient which produces a decrease in the immune response as was confirmed on testing CPIB on thymus-dependent antigens in haemolytic plaque assays.

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Section: Resultssupporting

confidence: 80%

Effect of clofibrate on the growth-kinetics of the murine P 1798(sc) lymphoma

Ubeira¹,

Prado²,

Puentes³

et al. 1983

Br J Cancer

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“…Clofibrate has recently been shown to promote hepatocarcinogenesis in rats [73], and it has been suggested that the interaction of an electrophilic glucuronide conjugate of clofibrate with tissue sulphydryl groups may have a role to play in this process [74]. However, bearing in mind the well characterised involvement of cytochrome P-450 in the metabolic activation of compounds to biologically reactive intermediates, one must attempt to evaluate the potential role of cytochrome P-452 in this hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Multiple forms of hepatic cytochrome P-450. Purification, characterisation and comparison of a novel clofibrate-induced isozyme with other major forms of cytochrome P-450

et al. 1984

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In the present studies, a novel form of highly purified cytochrome P-450 (cytochrome P-452) isolated from the hepatic microsomes of clofibrate-pretreated rats has been compared to the major isozymes isolated from the hepatic microsomes of rats pretreated with phenobarbital (cytochrome P-450) and 2-naphthoflavone (cytochrome P-447) using a number of biochemical criteria.The results show that these three isozymes exhibit marked structural differences from each other as judged by a complete lack of immunochemical cross-reactivity between the isozymes and the heterologous rabbit serum antibodies using Ouchterlony double diffusion, and non-identity between the limited proteolytic digestion maps of the three isozymes obtained in the presence of chymotrypsin, papain and Staphylococcus aureus V, proteases. Furthermore, the three isozymes exhibited clear differences in their monomeric molecular weights determined on calibrated sodium dodecyl sulphate/polyacrylamide gel electrophoresis in gels of varying acrylamide concentration. Substantial differences were also observed in the substrate specificities of the isozymes, which were reflected in differences in the turnover rates and positional selectivities of the hemoproteins for some model substrates. In addition, the isozymes differed in their substrate binding affinities and their ability to interact with purified hepatic microsomal cytochrome b,, as judged using difference spectrophotometry. Finally, subtle differences were detected in the ultraviolet visible absorbance spectra of the hemoproteins in the ferric, ferrous, and carbonmonoxyferrous states.Taken collectively, the above data provides compelling evidence that fundamental differences exist between these cytochrome P-450 isozymes, further establishing the uniqueness of the major form of cytochrome P-450 induced by clofibrate pretreatment.Cytochrome P-450 is the terminal hemoprotein component of the hepatic microsomal electron-transfer chain which functions in the oxidation of a structurally diverse number of xenobiotics and endogenous compounds [I]. Considerable evidence has been presented in support of the existence of Much confusion exists regarding the terminology of cytochrome P-450 isozymes primarily because there is no uniform classification system which has been adopted to make unequivocal assignments of the similarity between isozymes isolated in different laboratories. Accordingly, the above three isozymes described in this paper have been classified according to the wavelength maxima of the ferrouscarbonmonoxy adducts. In the current paper, limited use is made of the term cytochrome P-450 in a general sense to collectively indicate all the cytochrome P-450 isozymes. Where appropriate, we make extended use of the term cytochrome P-450 to indicate that major isozyme induced by phenobarbital pretreatment in rat liver. This is regarded as necessary because to make a distinction for this latter isozyme and rename it would add further confusion to the literature. Similarly, throughout this paper, the terms c...

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“…Treatment of CD rats with the peroxisome proliferator gemfibrozil led to a dosedependent increase in tumours of the interstitial cells of the testis [21], and tumours of the pancreas are also associated with several proliferators [22,23]. Consequently, the relationship between the induction of these proteins and other effects of the peroxisome proliferators in extrahepatic tissues remains intractable.…”

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confidence: 99%

Differential tissue‐specific expression and induction of cytochrome P450IVA1 and acyl‐CoA oxidase

Bell

Bars

Elcombe

1992

European Journal of Biochemistry

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We have examined the tissue-specific expression and inducibility of acyl-CoA oxidase and cytochrome P4501VA1 (P45OIVAl) RNA in rats. Groups of three rats were dosed daily by gavage with methylclofenapate at 25 mg/kg in 5 ml/kg corn oil for nine weeks, or were administered a vehicle control. P45OIVAl and acyl-CoA oxidase RNA were detected using an RNase protection assay. Similar levels of acyl-CoA oxidase RNA were present in control liver and kidney, but the level of this RNA in lung, muscle and testis was 6 -11%, and in pancreas was 0.13%, of that in liver. Treatment of rats with methylclofenapate led to an 11-fold induction of acyl-CoA oxidase RNA in liver and also produced a significant induction of this RNA in kidney, lung, muscle and testis of 1.7-fold, 1.3-fold, 2-fold and 1.7-fold, respectively. Acyl-CoA oxidase RNA was not induced in pancreas.P45OIVA1 RNA was present in control liver and also in kidney of control rats at 28% of the level in liver. In contrast to acyl-CoA oxidase RNA, P45OIVAl RNA was not detected in lung, pancreas or testis. Methylclofenapate treatment of rats led to an 18-fold induction of P45OIVA1 RNA in liver, and a sevenfold induction in kidney. Induction of P45OIVA1 was not detected in any of the other tissues examined. Quantification of the relative amounts of acyl-CoA oxidase and P45OIVAl RNA in control liver revealed that acyl-CoA oxidase RNA was present in a 17.5-fold molar excess over P45OIVA1 RNA.Western blotting with an antbP450IVA IgG revealed two bands of similar apparent molecular mass in liver and kidney microsomes, but not in microsomes from the testis of control rats. Methylclofenapate treatment of rats caused an increase in the intensity of these bands in microsomes from liver, but no induction was obvious in kidney. Immunocytochemical staining for both the microsomal P45OIVA and peroxisomal acyl-CoA oxidase proteins was restricted to the proximal convoluted tubule in the kidney cortex, with staining being most intense in the S3 region.The peroxisome proliferators were originally defined as a structurally diverse class of chemicals which induce proliferation of endoplasmic reticulum and peroxisomes, hyperpkdsia, hepatomegaly and carcinogenesis in rodent liver [l]. The mechanism whereby these changes occur is currently unclear, although two hypotheses are currently under investigation, as reviewed in [2]. The absence of a concrete mechanistic relationship between early events, such as hyperplasial peroxisome proliferation, and the late hepatocarcinogenic lesion, has focussed attention on the examination of the early events in the liver [2].Treatment with peroxisome proliferators leads to induction of a cytochrome P-450 which catalyses the o-hydroxylation of fatty acids [3 -51. This enzyme was purified [6] and cloned [7] from the rat and designated cytochrome P45OIVA1 [8], the first member of the complex P450IV gene family (e.g.

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Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-α-p-chlorophenoxyisobutyrate (clofibrate) in rats

Cited by 140 publications

References 24 publications

Effect of clofibrate on the growth-kinetics of the murine P 1798(sc) lymphoma

Effect of clofibrate on the growth-kinetics of the murine P 1798(sc) lymphoma

Multiple forms of hepatic cytochrome P-450. Purification, characterisation and comparison of a novel clofibrate-induced isozyme with other major forms of cytochrome P-450

Differential tissue‐specific expression and induction of cytochrome P450IVA1 and acyl‐CoA oxidase

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