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[The effect of pretreatment with enzyme inducers on the acute toxicity of DDT (1, 1-bis-(p-chlorophenyl)-2,2,2-trichloroethane) in rats].

A study was undertaken to investigate the influence of various hepatic enzyme inducers on the acute toxicity of the organohalogenated insecticide DDT. Adult female rats were pretreated with sodium phenobarbital (50 mg/kg/day during 5 days), 3-methylocholanthrene (20 mg/kg/day during 3 days), and norethandrolone (20 mg/kg/day during 14 days), and were then given 150 mk/kg of DDT per os. Phenobarbital was shown to lower the toxicity of DDT, norethandrolone had the opposite effect, and 3-methylcholanthrene was without any significant effect. After a phenobarbital pretreatment, the cerebral concentration of DDT was lowered, possibly as a result of an increased biotransformation of DDT to DDD in the liver. On the other hand, norethandrolone did not appear to modify the hepatic conversion of DDT to DDD, nor the cerebral concentration of DDT. Further studies are needed to explain the potentiating effect of norethandrolone on the acute toxicity of DDT.

Animals↗

Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol.

1. 19-Nor-17alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethynyloestradiol) or 17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one (norethindrone) but not 17alpha-ethyl-17beta-hydroxy-19-norandrost-4-en-3-one (norethandrolone) caused a time-dependent loss of cytochrome P-450 when incubated in vitro with rat liver microsomal fractions and NADPH-generating systems. 2. The enzyme system catalysing the norethindrone-mediated loss of cytochrome P-450 had many characteristics of the microsomal mixed-function oxidases. It required NADPH and air, and was inhibited by Co. However, it was unaffected by 1 mM-compound SKF 525A. 3. In microsomal fractions from phenobarbitone-pretreated rats the norethindrone-mediated loss of cytochrome P-450 was increased relative to controls. The norethindrone-mediated cytochrome P-450 loss was less pronounced when the animals were pretreated with 3beta-hydroxy-pregn-5-en-2-one 16alpha-carbonitrile (pregnenolone 16alpha-carbonitrile). Pretreatment with 3-methylcholanthrene rendered the animals resistant to the norethindrone effect. 4. Administration in vivo [100mg/kg, intraperitoneally] of norethindrone or ethinyl oestradiol also produced a time-dependent loss of liver cytochrome P-450. Norethandrolone had a similar, though much less-marked, effect. All three steroids lead to an induction of 5-aminolaevulinate synthase and an accumulation of porphyrins in the liver. 5. The loss of cytochrome P-450 and the accumulation of porphyrins in the liver 2 h after the administration of norethindrone to female rats was similar to that seen in males. 6. Rats pretreated with phenobarbitone and given norethindrone or ethynyloestradiol (100mg/kg, intraperitoneally) formed green pigments in their livers. These had characteristics similar to the green pigments produced in the livers of rats after the administration of 2-allyl-2-isopropylacetamide. No green pigments could be extracted from the livers of control rats or those given norethandrolone, oestradiol or progesterone.

5-Aminolevulinate Synthetase↗

Quantitative evaluation of virilizing activity of steroids by measuring morphological changes in uro-genital region of rats.

A new technique to measure the uro-genital parameters such as the lengths of urovaginal septum, corpora cavernosa and anogenital distance on the sagittal sections of the pelvic region of female fetus of rat under microscope equipped with a micrometer was developed. In the examination of 180 normal female fetuses on the 21st day of gestation, relationships were observed between the fetal body weight and the length of urovaginal septum as well as anogenital distance, but not on the length of corpora cavernosa. Following maternal subcutaneous administration of various doses of 17alpha-methyltestosterone between the 17th and 20th day of gestation, dose-dependent abridgment in urovaginal septum length and extensions in corpora cavernosa length and anogenital distance were observed in female fetus on the 21st day's examination. When these three parametars were calculated on the relative value to the fetal body weight, however, linear relationships against log-dose were observed in all parameters. Among these three parameters the abridgment in urovaginal septum was shown to be the most sensitive. A quantitative assay of virilizing activity of steroids in female fetuses was examined on rats treated subcutaneously with 17alpha-methyltestosterone and norethandrolone. Linear regressions against the log-doses of both steroids were demonstrated in urovaginal septum length, and parallelism was noted between both regression lines. The relative potency of norethandrolone to 17alpha-methyltestosterone calculated on urovaginal septum length was 0.354 with fiducial limits of 0.293-0.44l, and it was suggested that the virilizing activities of steroids can be evaluated quantitatively.

Animals↗

[Influence of various enzyme inductors and combinations of inductors on DDT residue elimination in rats].

A study was under-taken to investigate the influence of pretreatments with various hepatic microsomal enzyme inducers on the elimination of DDT residues in rats previously contaminated with p,p' -DDT at 5 mg/kg/day, during 20 days. The following inducers were used : phenobarbital (50 a mg/kg/day, i.p.), 3,4-benzopyrene (20 mg/kg/day, s.c.) and norethandrolone (20 mg/kg/day, s.c.), all given during 14 consecutive days. Each inducer was administered singly or in combination with the other two according to a 2 X 2 X 2 factorial experiment. The animals were then sacrificed for the measurement of p,p' -DDT, p,p' -DDD and p,p' -DDE residues in the blood, brain, abdominal fat, liver and kidneys. The results show that phenobarbital lowers markedly the concentration of total residues in the fat tissue and brain and that norethandrolone brings about a reduction of the residues in the blood, brain and kidneys, but not in the fat tissue. On the opposite, 3,4-benzopyrene produces an increase of the residues in the brain, liver and kidneys. Phenobarbital thus appears to be more efficacious than the other two inducers in facilitating the elimination of DDT residues from the fat tissue. In addition, it appears that under the experimental conditions used during this investigation, the elimination of DDT residues is not further accelerated by combining the inducers one with each other.

Abdomen↗

In vitro liver models are important tools to monitor the abuse of anabolic steroids in cattle.

Current veterinary residue analysis mainly focuses on the monitoring of residues of the administered parent compound. However, it is possible that larger amounts of metabolites are excreted and that they can have a prolonged excretion period. In order to unravel specific metabolic steps and to identify possible biological markers, two in vitro liver models were used, i.e. monolayer cultures of isolated hepatocytes and liver microsomes, both prepared from liver tissue of cattle. Chostebol, boldenone, norethandrolone (NE) and ethylestrenol (EES) were used as model substrates. Results show that the metabolic profiles derived from in vitro experiments are predictive for the in vivo metabolic pathways of the steroids evaluated in this study. By means of this strategy, it is possible to identify 17 alpha-ethyl-5 beta-estrane-3 alpha,17 beta-diol (EED) as a common biological marker for NE and EES. By in vivo experiments it was shown that EED is particularly important for the detection of the abuse of NE or EES because of its high excretion levels and its prolonged presence as compared with the parent compounds or any other metabolite.

Anabolic Agents↗

Chronic cholangitides: aetiology, diagnosis, and treatment.

A number of different chronic diseases affect the intrahepatic bile radicles or cholangioles. They include primary and secondary sclerosing cholangitis, primary biliary cirrhosis, chronic cholestatic drug jaundice, atresia, and carcinoma. Aetiological factors include infection, immunological changes, hormones, and congenital defects.Patients with chronic cholestasis have decreased bile salts in the intestinal contents and suffer from a bile salt deficiency syndrome. Failure to absorb dietary fat is managed by a low-fat diet and by medium-chain trigly-cerides which are absorbed in the absence of intestinal bile salts. Fat-soluble vitamin deficiencies are prevented by parenteral vitamins A, D, and K(1). Calcium absorption is defective, and improvement may follow intramuscular vitamin D, medium-chain triglycerides, a low-fat diet, and oral calcium supplements.In partial intestinal bile salt deficiency the anionic bile-salt-chelating resin cholestyramine controls pruritus though steatorrhoea increases. Pruritus associated with total lack of intestinal bile salts is managed by methyl-testosterone or norethandrolone, though the jaundice increases.

Bile Acids and Salts↗

Androgen therapy in aplastic anaemia: a comparative study of high and low-doses and of 4 different androgens. French Cooperative Group for the Study of Aplastic and Refractory Anemias.

A prospective randomized study of androgen therapy in aplastic anaemia (AA) was performed: 2 androgens (fluoxymesterone and norethandrolone) at high (1 mg/kg/d) and low (0.2 mg/kg/d) dose were studied on 110 patients; and 4 androgens given at high doses were objectively compared in 125 other cases. When patients are matched for AA severity there is an obvious efficiency of the high-dose androgens in the survival of the less severe cases of aplastic anaemia and in their haematological improvement. The data further show that, among the 4 androgens tested, fluoxymesterone is the most efficient and stanozolol the least. We conclude that androgen therapy is truly efficient in moderately severe aplastic anaemia and that fluoxymesterone (1 mg/kg/d) for 18 months should be chosen as reference drug to any new androgen therapy assay.

Adult↗