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Results for “Steroids, Chlorinated”

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At least 19 recordsLinked to original sources

PubMedDate not supplied

Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids.

The inactivation by 21-chlorinated steroids of rat liver cytochromes P-450 involved in the hydroxylation of progesterone and androstenedione has been investigated. Preincubation of intact liver microsomes from phenobarbital-treated rats with 21-chloropregnenolone, 21,21-dichloropregnenolone, or 21,21-dichloroprogesterone in the presence of NADPH caused a time-dependent decrease in progesterone 21-hydroxylase and in progesterone or androstenedione 6 beta-hydroxylase activity but had negligible or only minor effects on five other steroid hydroxylases. The compounds differed, however, with regard to the relative rate constants for inactivation of the 21- and 6 beta-hydroxylases. For example, 21,21-dichloroprogesterone and 21,21-dichloropregnenolone inactivated the progesterone 6 beta-hydroxylase at similar rates, but the dichloroprogesterone was a more effective inactivator of the 21-hydroxylase. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few isozymes of cytochrome P-450 may be a rational means of designing isozyme-selective inhibitors but that target and nontarget enzymes may not totally retain the regioselectivity they exhibit towards the underivatized substrate.

Animals↗

PubMed1988

Selective inactivation by 21-chlorinated steroids of rabbit liver and adrenal microsomal cytochromes P-450 involved in progesterone hydroxylation.

The inactivation by 21-chlorinated steroids of rabbit liver cytochromes P-450 involved in the hydroxylation of progesterone has been investigated in intact microsomes encompassing two phenotypes of 21-hydroxylase activity, two phenotypes of 16 alpha-hydroxylase activity, and three phenotypes of 6 beta-hydroxylase activity. In liver microsomes from outbred New Zealand White male rabbits exhibiting a high content of cytochrome P-450 1, 21,21-dichloropregnenolone caused a time- and NADPH-dependent loss of 21-hydroxylase activity. This loss of activity exhibited a number of characteristics of mechanism-based inactivation, including irreversibility, saturation with increasing inhibitor concentrations, and protection by substrate, and was also documented with purified P-450 1 in a reconstituted system. 21,21-Dichloropregnenolone caused no time-dependent loss of 6 beta-hydroxylase activity in microsomes from the New Zealand White rabbits or from control or rifampicin-treated rabbits of the inbred B/J strain. In contrast, in the microsomes from the B/J rabbits, some inactivation of the 16 alpha-hydroxylase was observed (k = 0.04 min-1), regardless of the rifampicin treatment. The other two compounds tested, 21-chloropregnenolone and 21,21-dichloroprogesterone, were less effective than the dichloropregnenolone as inactivators of cytochrome P-450 1. On the other hand, 21,21-dichloroprogesterone, but not 21,21-dichloropregneolone, caused a rapid time-dependent loss of 21-hydroxylase activity in rabbit adrenal microsomes. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few forms of cytochrome P-450 may be a rational means of designing selective inhibitors of the enzyme.

Adrenal Glands↗

PubMed2001

Three new chlorinated marine steroids, yonarasterols G, H and I, isolated from the okinawan soft coral, Clavularia viridis.

Three new chlorinated marine steroids, yonarasterols G, H and I, were isolated from the Okinawan soft coral, Clavularia viridis. Their structures including the absolute configuration were determined based on the results of spectroscopic analysis and chemical conversion.

Animals↗

PubMed1989

Studies on intestinal absorption, distribution and metabolism of 3 beta-chloro[4-14C]cholest-5-ene and 3 beta-chloro[4-14C]stigmast-5-ene in mice.

A method for the analysis of 3 beta-chloro steroids by high-performance liquid chromatography is described. These compounds are known to occur in commercial protein hydrolysates. The gastro-intestinal absorption, distribution and metabolism of chlorinated steroids were studied after their intragastric application to mice. At 2 hr after stomach intubation of 3 beta-chloro[4-14C]cholest-5-ene and 3 beta-chloro-[4-14C]stigmast-5-ene, large proportions of radioactivity had passed through the small intestine and were found to be concentrated in the contents of the caecum and colon. Very small amounts of 3 beta-chlorocholest-5-ene were absorbed by the intestinal mucosa and distributed to organs and tissues outside the alimentary canal, whereas intestinal permeability of 3 beta-chlorostigmast-5-ene was negligible. After administration of labelled 3 beta-chlorocholest-5-ene, the highest value of radioactivity, 120 Bq/g tissue, outside the intestinal tract was detected in liver. Altogether, less than 0.5% of the total radioactivity applied to the animals was found to be transported through the intestinal wall and less than 0.5% of the total radioactivity was detected in various metabolites. In general, 3 beta-chlorostigmast-5-ene was transported in smaller proportions and metabolized to a lesser extent than the corresponding cholesterol derivative. Moreover, metabolites of the two radioactive substrates formed by enzymatic attack of enteric micro-organisms were not detected in the contents of the caecum and colon. It appears that 3 beta-chlorinated steroids are fairly stable products that are metabolized poorly both by the cells of the intestinal mucosa and by enteric micro-organisms of mice.

Animals↗

PubMed1986

Assignment of anabolic-androgenic and antiandrogenic properties to some chlorine-substituted steroids on the basis of their binding characteristics to the androgen receptor of the rat seminal vesicle.

In this study we investigated the affinity of several 4-chlorinated and 1-ene derivatives of 17 alpha-methyltestosterone (MT) and 17 alpha-methyl-5 alpha-dihydrotestosterone (MDHT) to the androgen receptor, and, additionally, the effect of a few MT-derived steroids on the activity of the 5 alpha-reductase enzyme present in the rat seminal vesicle. From our results we conclude, that delta 1 or/and delta 4 double bonds in ring A counteract the inhibition of receptor-binding caused by chlorine-substitution at C4; the dissociation of myotropic and androgenic effects [= M/A dissociation] of 4-chloro-MT (as compared to MT) is due to its inactivation by 5 alpha-reductase in androgen target organs and/or to the inhibition of the conversion of endogenous testosterone to DHT; the M/A dissociation of 1-ene-MT and 4-chloro-1-ene-MT may be explained by their inability to be activated by 5 alpha-reductase; for the same reason, M/A dissociation can be assigned to the effects of 4 alpha-chloro-1-ene-DHT. We determined the short-term and long-term competition of cyproterone acetate and chlormadinone acetate with [3H]DHT for receptor binding at 0 degrees C and showed, that the complexes formed by these antiandrogens with the androgen receptor have equally reduced stabilities compared to the DHT-receptor complex.

Anabolic Agents↗

PubMed1976

Interactions of chlorinated hydrocarbons with steroid hormones.

Effects of chlorinated hydrocarbons of the DDT class in mammals were examined. Two effects were considered: a) induction of hepatic mixed function oxidase (MFO), and b) estrogenic activities. The induction of MFO was discussed primarily with reference to the enhancement of steroid hydroxylation. In turn, the increase in steroid hydroxylation by chlorinated hydrocarbons was usually accompanied by a decrease in the biological activity of endogenous and administered steroid hormones. The estrogenic activity of chlorinated hydrocarbons was found to reside primarily in the o,p'-DDT (a major contaminant of technical grade DDT). The mechanism of the estrogenic activity by DDT homologs was explored. It appears that o,p'-DDT acts like estradiol (E2). Similarly to E2, o,p'-DDT binds to the uterine cytosolic receptor. Furthermore, like E2, o,p'-DDT is a potent inducer of certain uterine enzymes. For instance induction of ornithine decarboxylase of about 200-fold was observed with a high dose (250 mg/kg body wt); however as little as 5 mg/kg of o,p'-DDT exhibited marked induction of this enzyme--about threefold. The above activities of the chlorinated hydrocarbons were considered with respect to the potential long-term toxic effects which these compounds might elicit.

Animals↗

PubMed1994

3 beta-Chlorosteroids: artefacts and possible contaminants in food and feed--toxicological effects in mice.

3 beta-Chlorosteroids, such as cholesteryl beta-chloride and sitosteryl beta-chloride, are formed during the production of protein hydrolysates, which are useful flavour enhancers. These chlorinated steroids may also attract attention as environmental contaminants if they are released from liquid crystal display devices. The effects of orally administered 3 beta-chlorosteroids were tested in female NMRI mice. The animals were fed cholesteryl beta-chloride or sitosteryl beta-chloride at doses of 1 mg and 10 mg/animal/day, that is, 33 mg and 330 mg/body weight/day, over a period of 3 months. Feed intake, body weight and organ weights of the animals, as well as concentration of 3 beta-chlorosteroids in faeces and various organs and tissues showed that cholesteryl beta-chloride and sitosteryl beta-chloride are not acutely toxic compounds. However, chronic toxicity cannot be excluded because small amounts of 3 beta-chlorosteroids, in particular cholesteryl beta-chloride, were absorbed by the intestinal tract and accumulated in adipose tissue. Histopathological examination of sections of organs and tissues showed no indication of irreversible cell damage in the stomach, duodenum, liver, kidneys and spleen caused by the chlorinated steroids.

Absorption↗

PubMed1994

Aragusterol C: a novel halogenated marine steroid from an Okinawan sponge, Xestospongia sp., possessing potent antitumor activity.

A novel chlorinated steroid, aragusterol C, was isolated from an Okinawan marine sponge of the genus Xestospongia. The compound strongly inhibited the proliferation of KB cells in vitro, and also showed potent in vivo antitumor activity against L1210 cells in mice. The complete structure of aragusterol C was determined by spectroscopic analysis and X-ray crystallographic analysis.

Animals↗

PubMed1996

Synthesis of some analogues of blattellastanoside A, the steroidal aggregation pheromone of the German cockroach.

Blattellastanoside A, the aggregation pheromone of the German cockroach, is a chlorinated steroid glucoside with the 5 beta-stigmastane skeleton. Its analogues were synthesized in order to clarify the structure-activity relationship. They are 1a with the 5 beta-cholestane skeleton, 1b with the 5 beta-androstane skeleton, 1c with a fluorine substituent instead of the chlorine and 1d with a beta-D-galactopyranose instead of the beta-D-glucopyranose of the original pheromone. Their bioassay shows that 1a and 1c are active, while 1b and 1d are totally devoid of pheromone activity. The aglycone of blattellastanosides A and B were active.

Animals↗

PubMed1981

Synthesis of dehydroepiandrosterone sulfatide and 16 alpha-halogenated steroids.

Dehydroepiandrosterone sulfatide was prepared in a 68% yield by the reaction of 5-androstene-3 beta-ol-17-one 3 sulfate (silver salt) with dipalmitoyl alpha-iodopropylene glycol. The sulfatide was found to be a more potent inhibitor of human glucose-6-phosphate dehydrogenase than dehydroepiandrosterone. 16 alpha-Halogenated steroids also were prepared by direct halogenation of the steroid or indirect halogenation of an appropriate steroidal intermediate. Among various halogenated steroids, 16 alpha-bromoepiandrosterone was 50 times as potent as dehydroepiandrosterone as an inhibitor of glucose-6-phosphate dehydrogenase.

Animals↗

PubMed1971