TY - JOUR
T1 - Investigations on the mechanism of the hypocholesterolemic action of diethylhexyl phthalate in rats
AU - Nair, Nandini
AU - Kurup, C. K.Ramakrishna
N1 - Funding Information:
The results presented in this paper give convincing evidence that the hypocholesterolemic action of DEHP arises largely from the ability of the compound in vivo to stimulate the degradative removal of the sterol as bile acids. The stimulation of the activity of the rate-limiting hydroxylase enzyme and the proliferation of mitochondria in the liver con- tribute to this process. The contribution of the inhibition of HMGCoA reductase in determining the level of serum cholesterol may be partial in view of the hepatomegalic effect of DEHP which tends to compensate for this effect to a certain extent. A comparison of the action of DEHP with that of other hypolipidemic compounds may not be out of place. It would appear that these compounds act through different mechanisms. Thus, D-thyroxine which is widely used as an anti-hypercholesterolemic drug does not directly influence cholesterol biogenesis but improves elimination primarily as neutral sterols and less significantly as bile acids \[43, 50, 51\]. There is no convincing evidence that poly-unsaturated lipids exert any inhibitory influence on cholesterol biosynthesis. Their hypocholesterolemic action appears to rest to a small extent on interference with absorption and enhanced withdrawal into tissues \[50\]b ut largely on increased biliary excretion of cholesterol and bile acids \[52\].B ile acid sequestrants like cholestyramine interrupt entero-hepatic circulation of bile and cause a several-fold increase in faecal excretion of cholesterol \[431. The antihypercholesterolemic drug clofibrate, many of whose effects on the liver are mimicked by DEHP, inhibits HMGCoA reductase and cholesterol synthesis from acetate but not from mevalonate \[53, 54\]. However, degradative removal of cholesterol in the form of bile as the major cause of the hypo-cholesterolemic action of the drug was high-lighted by Kritchevsky and associates \[29\]. The hepa-tomegalic and mitochondria-proliferating actions of the drug play a decisive role in this process, It may be pointed out that the cholesterol side chain oxidizing capacity of mitochondria did not increase with administration of either clofibrate or DEHP, the higher rate of bile excretion in both cases being accomplished by the increase in mitochondrial population, However, the large increase in the biliary excretion of free cholesterol in clofibrate-treated animals and patients \[43, 55, 56\] may be contrasted with a large decrease in the content of cholesterol in the bile of DEHP-administered animals. Since high concentrations of cholesterol in bile tend to produce gall stones, DEHP should be free of this harmful effect if used in therapy. There is no evidence that clofibrate administration increases microsomal 7n-hydroxylase activity \[57\]. It is interesting that in DEHP-administered animals, the synthesis of cholesterol was inhibited and the decay rate was enhanced, but the concentration of cholesterol per gram of liver did not suffer any significant decrease (1.7 =0.03 and 1.5 +-0.04 mg cholesterol/g liver in control and 30-day DEHP-administered animals respectivelyt. Administration of clofibrate also does not bring about any significant decrease in the content of cholesterol in liver \[57\].T his conforms to the view that the cholesterol content of liver is finely regulated \[55\]. Under conditions of decreased synthesis and enhanced degradation, homeostasis is achieved bv enhanced mobilization of tissue cholesterol via the serum \[43\]. Acknowledgements--Financial support from the University Grants Commission, Government of India. New Delhi, is acknowledged.
PY - 1986/10/15
Y1 - 1986/10/15
N2 - The plasticizer di(2-ethylhexyl)phthalate (DEHP), used widely in the manufacture of food packages and medical plastic devices, depressed serum cholesterol (40%) and proliferated hepatic mitochondria (100%) when administered in the diet (2%, w/w) to the rat. Microsomes isolated from the livers of animals administered DEHP showed lowered specific activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (50%). The incorporation of acetate but not of mevalonate into hepatic cholesterol was decreased (52%) in these animals. The release of bile acids was greatly enhanced (100%), and the activity of cholesterol 7α-hydroxylase, the regulatory enzyme in the pathway of bile acid formation, was stimulated (70%) on DEHP administration. Even though the capacity of mitochondria to oxidize the side chain of cholesterol was not enhanced in DEHP-fed animals, the larger population of mitochondria would ensure that the amount of cholesterol oxidized per gram of liver was significantly higher.
AB - The plasticizer di(2-ethylhexyl)phthalate (DEHP), used widely in the manufacture of food packages and medical plastic devices, depressed serum cholesterol (40%) and proliferated hepatic mitochondria (100%) when administered in the diet (2%, w/w) to the rat. Microsomes isolated from the livers of animals administered DEHP showed lowered specific activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (50%). The incorporation of acetate but not of mevalonate into hepatic cholesterol was decreased (52%) in these animals. The release of bile acids was greatly enhanced (100%), and the activity of cholesterol 7α-hydroxylase, the regulatory enzyme in the pathway of bile acid formation, was stimulated (70%) on DEHP administration. Even though the capacity of mitochondria to oxidize the side chain of cholesterol was not enhanced in DEHP-fed animals, the larger population of mitochondria would ensure that the amount of cholesterol oxidized per gram of liver was significantly higher.
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U2 - 10.1016/0006-2952(86)90610-6
DO - 10.1016/0006-2952(86)90610-6
M3 - Article
C2 - 3768033
AN - SCOPUS:0023030593
SN - 0006-2952
VL - 35
SP - 3441
EP - 3447
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 20
ER -