The Effect of Peroxisome Prouferators on Microsomal. Peroxisomal, and Mitochondrial Enzyme Activities in the Liver and Kidney

Hawkins, Janet M.; Jones, William E.; Bonner, Frank W.; Gibson, Gordon

doi:10.3109/03602538708994130

Cited by 208 publications

(70 citation statements)

References 207 publications

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“…Unlike rats, pigeons did not respond to treatment with Aroclor 1254 by specifically increasing the hepatic woxidation of lauric acid. The 2-fold increase observed with pigeons in the formation of 1 1-hydroxylauric acid in response to Aroclor 1254 treatment is similar to that observed with phenobarbital-treated rats [4], and is therefore likely to be due to the induction of several forms of cytochrome P-450 that have the ability to hydroxylate lauric acid at the w -1 position [2].…”

Section: Resultssupporting

confidence: 61%

“…This hepatic w-oxidation of lauric acid is specifically enhanced in animals in which cytochrome P-452 has been induced, and lauric acid is known to be an excellent substrate to assay the induction of this cytochrome [4]. Previous work [5] had shown that treatment with the hypolipidemic drug clofibrate resulted in a specific 28-fold induction of hepatic microsomal w-oxidation of lauric acid in CD-l mice and marmoset monkeys, whereas phenobarbital treatment increased 1 1-hydroxylation of lauric acid 2-fold but depressed 12-hydroxylation Table 1 Effect of polychlorinated biphenyl (PCB)-mediated induction of hepatic cytochrome P-450 on w-and w -1 hydroxylation of lauric acid five days after treatment with Aroclor 1254 of lauric acid to 75% of control values.…”

Section: Resultsmentioning

confidence: 99%

“…For example, there is evidence that arachidonate is metabolized by purified cytochrome P-452 at the w and w i 1 positions [4]. In addition, immunochemical evidence for the induction of a number of different forms of cytochrome P-450 in animals in response to environmental levels of PCB pollution [8] raises the question of whether high levels of contamination with PCBs in humans could alter their response to treatment with hypolipidemic drugs.…”

Section: Speciesmentioning

confidence: 99%

“…It is not known whether PCB mixtures have the ability to induce cytochrome P-452, which is specifically induced in hepatic microsomes by hypolipidemic drugs such as clofibrate and by phthalate ester plasticisers [4]. Increased Woxidation of the model substrate lauric acid (12 : 0) to 12-hydroxylauric acid by hepatic microsomes in response to treating rats with clofibrate has been attributed to the induction of cytochrome P-452-linked enzyme activities [4].…”

Section: Introductionmentioning

confidence: 99%

“…Increased Woxidation of the model substrate lauric acid (12 : 0) to 12-hydroxylauric acid by hepatic microsomes in response to treating rats with clofibrate has been attributed to the induction of cytochrome P-452-linked enzyme activities [4]. In contrast, treating rats with phenobarbital increases the (J -1 oxidation of lauric acid to 11 -hydroxylauric acid by hepatic microsomes, but does not increase the LJ-oxidation of this substrate [5].…”

Section: Introductionmentioning

confidence: 99%

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Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

et al. 1989

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We have examined the ability of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) to induce hepatic cytochrome P-4X?-linked enzyme activities in rat and pigeon liver five days after its intraperitoneal injection. The results provide evidence that, at the doses used, Aroclor 1254 induces cytochrome P-452-linked enzyme activities in rats, but not in pigeons. This inductive effect was previously regarded as being specific for hypolipidemic drugs and phthalate ester plasticisers.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Speciesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

et al. 1989

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Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

Ahmad

Caldwell

1994

Chirality

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The significance of disturbances of lipid metabolism caused by xenobiotic acyl-CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2-phenylpropionic acid (2-PPA), the (R)-enantiomer of which is converted to the acyl-CoA in rats while its (S)-antipode is not. rac-2-PPA (250 mg/kg/day ip x 3) was shown to be an hepatic peroxisomal proliferator in male Sprague-Dawley rats on the basis of increases in microsomal cytochrome P-450 content and lauric acid hydroxylation and hepatic CN(-)-insensitive palmitoyl-CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose-response relationships for these biochemical changes. The (R)- and (S)-enantiomers were administered at a dose of 50 mg/kg/day ip x 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip x 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip x 3 of its two component isomers. The stereoselectivity of acyl-CoA formation from the enantiomers of 2-PPA was confirmed by their differential inhibition of microsomal palmitoyl-CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl-CoA of 2-PPA plays any role in the peroxisomal proliferation which this compound causes in the rat.

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Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: Review and hypothesis

1993

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Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.

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The Effect of Peroxisome Prouferators on Microsomal. Peroxisomal, and Mitochondrial Enzyme Activities in the Liver and Kidney

Cited by 208 publications

References 207 publications

Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: Review and hypothesis

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