ABSTRACT
Modifications of 6-oxa-D-homo-8alpha-analogues of steroid estrogens were found to lead to a complete loss of the uterotropic and hypertriglyceridemic activities. These compounds may be promising for the design on their basis of inhibitors of the steroid hormone metabolism and transporters of other compounds to the estrogen target organs.
Subject(s)
Estrogens/chemical synthesis , Steroids/chemical synthesis , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Bone and Bones/anatomy & histology , Bone and Bones/drug effects , Cholesterol/blood , Estrogens/chemistry , Estrogens/pharmacology , Female , Organ Size/drug effects , Ovariectomy , Rats , Rats, Sprague-Dawley , Receptors, Progesterone/biosynthesis , Stereoisomerism , Steroids/chemistry , Steroids/pharmacology , Structure-Activity Relationship , Sulfatases/antagonists & inhibitors , Triglycerides/blood , Uterus/anatomy & histology , Uterus/drug effects , Uterus/metabolismABSTRACT
Models of experimental dyslipoproteinemias have been developed by using non-inbred rats (males and females) and guinea-pigs. Administration of cholesterol (C) with fats and supplementation of 4-hydroxy-6-methyl-2-thiouracil to male rats and that of C in the mixture of fats to guinea-pigs have been demonstrated to lead to the development of atherogenic dyslipoproteinemias. Genfibrozil, cholestyramine and vasosan II, a new pectin-enriched formulation, promoted normalization of the impaired serum lipoprotein spectrum caused by exogenous C administration. Bilateral ovariectomy in female rats induced atherogenic dyslipoproteinemia. The use of the estrogen derivative methyl ether of 6-oxa-D-homo-8-isoestrone normalized lipid and lipoprotein metabolic disturbances.
Subject(s)
Hyperlipoproteinemias/drug therapy , Hypolipidemic Agents/therapeutic use , Animals , Disease Models, Animal , Evaluation Studies as Topic , Female , Guinea Pigs , Male , RatsSubject(s)
Estrone/therapeutic use , Hyperlipidemias/drug therapy , Animals , Cholesterol/blood , Cholesterol/metabolism , Esters , Estrone/analogs & derivatives , Female , Hyperlipidemias/metabolism , Lipoproteins/blood , Lipoproteins/metabolism , Male , Methylation , Ovariectomy , Rats , Triglycerides/blood , Triglycerides/metabolismABSTRACT
Ovariectomy of rats resulted in biphasic increase of the blood plasma cholesterol (on days 42-54, 70), the alteration of lipoprotein spectrum. The administration to ovariectomized rats of methyl ether 6-oxy-D-homo-8-isoestrone in a dose of 0.01 mg/kg brought about lowering of serum cholesterol and normalization of lipoproteins spectrum. The above trends were not observed after introduction of 0.01 mg/kg estradiol.
Subject(s)
Estrone/analogs & derivatives , Estrone/pharmacology , Homosteroids , Lipids/blood , Lipoproteins/blood , Lipoproteins/drug effects , Ovary/physiology , Animals , Drug Evaluation, Preclinical , Estrone/therapeutic use , Female , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Hypercholesterolemia/etiology , Ovariectomy , RatsABSTRACT
Racemic 16,16-dimethyl-D-homo-8-isoestrone methyl ester (substance 1) was shown to decrease the content of cholesterol in blood serum and liver tissue of animals with induced hyperlipidemia (rats, guinea pigs, rabbits) as well as to decrease the rate of atherosclerotic impairments in rabbit aorta. As distinct from usual estrogen, the substance I did not cause hypertriglyceridemia but normalized triglycerides in blood and liver tissue. Substance I exhibited low toxic effects.
