Peroxisomal effects of phthalate esters in primary cultures of rat hepatocytes

Gray, Tim J.B.; Lake, Brian G.; Beamand, J.A.; Foster, John R.; Gangolli, S.D.

doi:10.1016/0300-483x(83)90115-4

Cited by 66 publications

(20 citation statements)

References 24 publications

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“…Maximal induction was observed at a dose of 0.25 mM. In contrast, no systematic change in cyanideinsensitive palmitoyl CoA oxidation was seen in hepatocytes treated with MnHP or, in agreement with Gray et al (21), in hepatocytes treated with MnOP. Hepatocytes treated with 0.25 mM MnHP or MnOP, unlike hepatocytes treated with 0.25 mM MEHP, showed signs of systematic toxicity such as blebbing and vacuolation although there was no increase in cell death as assessed by leakage of lactate dehydrogenase into the medium.…”

Section: Experiments On Isolated Hepatocytessupporting

confidence: 90%

Effects of phthalic acid esters on the liver and thyroid.

Hinton¹,

Mitchell²,

Mann³

et al. 1986

Environ Health Perspect

127

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The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P450 isoenzyme(s) catalyzing w oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fall to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid.The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

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Section: Experiments On Isolated Hepatocytessupporting

confidence: 90%

Effects of phthalic acid esters on the liver and thyroid.

Hinton¹,

Mitchell²,

Mann³

et al. 1986

Environ Health Perspect

127

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“…Induction of the 80 kD polypeptide by CPIB in cultured hepatocytes has been reported; however, neither quantitation or concentration-dependent data were presented (39). Our results show that cultured hepatocytes exposed to CIPRO and CPIB respond with concentration-dependent increases in the amount of this 80 kD polypeptide and the activity of CAT.…”

Section: Discussioncontrasting

confidence: 73%

Characterization of ciprofibrate and clofibric acid as peroxisomal proliferators in primary cultures of rat hepatocytes

Feller¹,

Singh²,

Shirhatti³

et al. 1987

Hepatology

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We have determined the comparative activities of peroxisomal proliferators, ciprofibrate and clofibric acid on various hepatic parameters associated with endoplasmic reticulum, mitochondria and peroxisomes in primary cultures of rat hepatocytes. We have measured the activities of carnitine acetyltransferase and fatty acylCoA oxidase, and the amount of 60 and 80 kD polypeptides as biochemical markers of the peroxisomal function; laurate hydroxylase and cytochrome P-450 as markers of the endoplasmic reticulum; and carnitine palmitoyltransferase as a marker of mitochondria in primary cultures of hepatocytes. Ciprofibrate (0.01 to 0.3 mM) and clofibric acid (0.1 to 3 mM) produced similar changes in several components of cultured hepatocytes within 72 hr. Increases of protein (18 and 11%), carnitine palmitoyltransferase (23 and 97%), cytochrome P-450 (37 and 49%), carnitine acetyltransferase (484 and 614%), fatty acylCoA oxidase (529 and 931%) and laurate hydroxylase (624 and 671%) were obtained in hepatocytes after a 72-hr exposure to 0.1 mM ciprofibrate and 1.0 mM clofibric acid, respectively. In cultured hepatocytes, ciprofibrate was about 30-fold more active than clofibric acid for the stimulation of carnitine acetyltransferase, laurate hydroxylase and fatty acylCoA oxidase activities. Ciprofibrate was also more potent than clofibric acid as an inducer of the 60 and 80 kD proteins in hepatocytes. The maximal drug-induced increases in carnitine acetyltransferase activity were not additive, and the induction of carnitine acetyltransferase by ciprofibrate was blocked by addition (1 micrograms per ml) of cycloheximide or actinomycin D. Changes in protein and RNA synthesis preceded the drug-induced increases of carnitine acetyltransferase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Certainly, in the cell culture studies no compound was truly negative, in that they all produced some stimulation of enzyme activities. We have previously demonstrated increases in peroxisome numbers in rat hepatocyte cultures after treatment with MEHP and other peroxisome proliferators (14,26,27). Although hepatocyte cultures cannot compensate for differences in compound phar- macokinetics as well as possible differences between in vivo and in vitro metabolism; the present studies indicate the potential usefulness of cell cultures as a rapid and economical screen for the induction of peroxisomal enzyme activities.…”

Section: Discussionmentioning

confidence: 57%

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

Lake¹,

Gray²,

Gangolli³

1986

Environmental Health Perspectives

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The hepatic effects of phthalate esters and related compounds on peroxisomal and microsomal enzyme activities were investigated in the intact animal and in primary hepatocyte cultures. In vitro studies with a series of phthalate monoesters demonstrated structure activity differences in the induction of the specific peroxisomal marker KCN-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. These effects could be reproduced in vivo, and potency differences were also observed between di(2-ethylhexyl) phthalate (DEHP) and its straight-chain isomer, di-n-octyl phthalate. In in vivo studies, DEHP, mono(2-ethylhexyl) phthalate, and clofibrate/clofibric acid produced large increases in liver size and peroxisomal enzyme activities in Sprague-Dawley rats and Chinese hamsters, but had less effect in Syrian hamsters. These effects could be largely reproduced in vitro where good responses were obtained with rat and Chinese hamster hepatocytes, but either little or no effect with Syrian hamster and DunkinHartley guinea pig hepatocytes. Both DEHP and clofibrate appeared to induce similar form(s) of microsomal cytochrome P-450 which exhibited a high specificity towards lauric acid hydroxylation. With a range of hypolipidemic agents, including phthalate monoesters, a good correlation was observed between the induction of peroxisomal and microsomal enzyme activities in rat hepatocyte cultures. These results thus demonstrate a good relationship between the in vivo and in vitro effects of phthalate esters and related compounds and suggest that hepatocyte cultures may be useful for further studies on the hepatic effects of peroxisome proliferators.

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Peroxisomal effects of phthalate esters in primary cultures of rat hepatocytes

Cited by 66 publications

References 24 publications

Effects of phthalic acid esters on the liver and thyroid.

Effects of phthalic acid esters on the liver and thyroid.

Characterization of ciprofibrate and clofibric acid as peroxisomal proliferators in primary cultures of rat hepatocytes

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

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