Steroid diamine-nucleic acid interactions: partial insertion of dipyrandium between unstacked base pairs of the poly(dA-dT) duplex in solution.
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We report on an NMR investigation of steroid diamine.nucleic acid complexes as a function of phosphate-to-drug ratios in aqueous solution in order to evaluate the structural and kinetic aspects of the binding of a nonintercalative drug to a synthetic DNA in solution. The nonexchangeable proton chemical shift parameters for the dipyrandium.poly(dA-dT) complex demonstrate unstacking of base pairs and partial insertion of the steroid diamine at the complexation site. The chemical shifts and linewidths of the exchangeable protons as a function of pH demonstrate that the base pairs are intact but partially exposed to solvent at the steroid diamine binding site. The phosphorus chemical shifts suggest that the base pairs unstack upon complex formation without changes in the omega,omega' polynucleotide backbone torsion angles. The NMR line shape parameters require rapid exchange of the steroid diamine among potential binding sites and are consistent with greater segmental flexibility in the complex compared to the synthetic DNA in solution. The NMR experiments are discussed in relation to Sobell's proposed model [Sobell, H.M., Tsai, C.C., Gilbert, S.G., Jain, S.C. & Sakore, T.D. (1976) Proc. Natl. Acad. Sci USA 73, 3068-3072] for the steroid diamine-DNA complex. (+info)
Biotransformation of bile acids by clostridia.
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The metabolism of bile acids by nuclear dehydrogenating clostridia (NDC) was studied. NDC were able to desaturate the A-ring of 5 beta-cholan-3-oxo-24-oic acid, 12 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 7 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 6 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 7 alpha, 12 alpha-dihydroxy-5 beta-cholan-3-oxo-24-oic acid, 3,12-dioxo-5 beta-cholan-24-oic acid but not 3,6-dioxo-5 beta-cholan-24-oic acid, 3,7-dioxo-5 beta-cholan-24-oic acid and 3,7,12-trioxo-5 beta-cholan-24-oic acid. In each case the sole product possessed a 4-ene-3-one structure. Desaturation of bile acids was more efficient than that of androstanes. NDC are, therefore, capable of introducing double bonds into the nucleus of bile acids as well as that of androstanes. The physiological significance of such reactions in relation to large bowel cancer has yet to be elucidated. (+info)
Pseudomonas mutant strains that accumulate androstane and seco-androstane intermediates from bile acids.
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Transposon mutant strains which were affected in bile acid catabolism were isolated from four Pseudomonas spp. Two of the mutant groups isolated were found to accumulate 12 alpha-hydroxyandrosta-1,4-diene-3,17-dione as the major product from deoxycholic acid. Strains in one of these two groups were able to grow on steroids such as chenodeoxycholic acid, which lacks a 12 alpha-hydroxy function, whereas the one member of the second group could not. With chenodeoxycholic acid, this latter strain accumulated a yellow muconic-like derivative, tentatively identified as 3,7-dihydroxy-5,9,17-trioxo-4(5),9(10)-disecoandrosta-1(10)2 -dien-4-oic acid. Members of two further mutant groups accumulated either 12 beta-hydroxyandrosta-1,4-diene-3,17-dione or 3,12 beta-dihydroxy-9(10)-secoandrosta-1,3,5(10)-triene-9,17-dione as the major product from deoxycholic acid. The relationship between the catabolism of m- and p-cresol, 3-ethylphenol and the bile acids was also examined. (+info)
Antagonism of inhibitory amino acids by the steroid derivative RU5135.
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The steroid derivative RU5135 has been tested for its ability to antagonize glycine and the gamma-aminobutyric acid (GABA) analogue muscimol on isolated preparations of rat optic nerve and cuneate nucleus, respectively. On the cuneate nucleus, RU5135 antagonized muscimol in a competitive manner with a pA2 value of 8.31. RU5135 shared a common site of action with bicuculline that was separate from the picrotoxin site. On the optic nerve, RU5135 antagonized glycine with a pA2 of 7.67. It shared a common site of action with strychnine. (+info)
Androgen dynamics in vitro in the normal and hyperplastic human prostate gland.
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The dynamics of uptake and metabolism in vitro of androgens by normal and hyperplastic human prostate glands was studied by means of a new experimental design proposed by Gurpide & Welch (1969). Prostate slices were perfused with a medium containing [(3)H]testosterone and [(14)C]androstenedione, or 5alpha-dihydro-[(3)H]testosterone and [(14)C]testosterone. The entry into the slices, the irreversible metabolism, the conversion between the compounds and the tissue retention or ;uptake' of the steroids were measured at the steady state. A similar portion of the three androgens entered the tissue and was irreversibly metabolized. Conversion of testosterone into 5alpha-dihydrotestosterone was much greater than the interconversion of testosterone and androstenedione. The prostate slices retained 5alpha-dihydrotestosterone at a concentration three times that in the medium, whereas testosterone and androstenedione were retained to a smaller extent. At a steroid concentration of 0.11mumol/l in the medium, the various parameters did not differ significantly in experiments performed with slices from normal and hyperplastic glands. When the steroid concentration in the medium was increased tenfold, however, a difference between normal and hyperplastic glands was evident. The normal glands increased the uptake and metabolism proportionally to the elevation of the steroid concentration in the medium. In the hyperplastic glands the entry and metabolism lagged behind the increase in steroid supply, whereas the tissue uptake became disproportionately high. The possible causes of this finding are discussed. (+info)
The biosynthesis of some androst-16-enes from C21 and C19 steroids in boar testicular and adrenal tissue.
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1. The formation of androst-16-enes from [4-(14)C]progesterone has been investigated with long-term incubations and short-term kinetic studies. After 4hr., 1.7 and 10.3% respectively of 3alpha- and 3beta-hydroxy-5alpha-androst-16-enes were formed in boar testis minces, but much smaller yields were obtained in boar adrenal. Both tissues formed small quantities of androsta-4,16-dien-3-one. 2. The amounts of androst-4-ene-3,17-dione and testosterone isolated were small, suggesting that androst-16-ene formation may occur preferentially in the boar testis. 3. In the absence of tissue no radioactive androst-16-enes were formed. 4. Incubation of both [4-(14)C]pregnenolone and [7alpha-(3)H]progesterone resulted in 3alpha- and 3beta-hydroxy-5alpha-androst-16-enes containing (3)H/(14)C ratios of near unity and confirmed that both C(21) steroids were precursors. A similar incubation with 17alpha-hydroxy[4-(14)C]-progesterone and [7alpha-(3)H]progesterone gave the same Delta(16)-alcohols, but they contained only (3)H, indicating that side-chain cleavage of pregnenolone and progesterone occurred before 17alpha-hydroxylation. 5. Dehydroepiandrosterone, testosterone, testosterone acetate and 16-dehydroprogesterone were not found to be precursors of Delta(16)-steroids. 6. A pathway is proposed for the biosynthesis of 3alpha- and 3beta-hydroxy-5alpha-androst-16-enes from pregnenolone and progesterone; this may involve androsta-4,16-dien-3-one as an intermediate, but excludes 17alpha-hydroxyprogesterone, testosterone and dehydroepiandrosterone. (+info)
Responses of staphylococci to androgens.
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The reported regulatory activities of hormones on mammalian cells suggest that a hormonal effect may be of importance in the host-parasite relationship of staphylococci. Male 6-month-old rabbits of similar genetic constitution were given subcutaneously 20 mug of androgens in saline containing 1% ethyl alcohol. Control rabbits received 1% ethyl alcohol in saline. At 5 to 10 min after administration of androgens, the rabbits were bled by cardiac puncture, and the serum was separated and incubated with standardized suspensions of Staphylococcus aureus serotypes I to XIII. It was found that S. aureus grew more luxuriantly in the sera of the control rabbits than in the sera of androgen-treated animals. With tryptic soy broth as a culture medium, a concentration 150- to 300-fold (30 to 40 mug/ml) higher than that achieved in the blood of an androgen-treated rabbit was required to yield an equivalent effect. In addition, the androgen-staphylococcal interaction has been studied with regard to experimentally induced furunculosis, the uptake of androgens by staphylococci and steroid molecular structure and antimicrobial activity. The data indicate that androgens may play a role in protection against staphylococcal infection. (+info)
Metabolism of C 19 -steroids by homogenates of normal rat and mouse adrenal tissue and of the Snell transplantable rat adrenocortical tumour 494.
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C(19)-steroid metabolism in homogenates of adrenal tissue from rats and mice has been studied. Production of these compounds from [7alpha-(3)H]cholesterol by rat adrenal tissue appeared to follow a route independent of pregnenolone. The major products of [7alpha-(3)H]-dehydroepiandrosterone metabolism by rat adrenal tissue were 5alpha-reduced steroids, principally androsterone, epiandrosterone and 5alpha-androstanedione. No differences in metabolism of [7alpha-(3)H]dehydroepiandrosterone or [4-(14)C]pregnenolone were detected between adrenal tissue from Sprague-Dawley, Wistar and Osborne-Mendel rats, but experiments with the Snell rat adrenocortical tumour 494 showed that this tissue had low 5alpha-reductase activity. In contrast, the major products of [7alpha-(3)H]dehydroepiandrosterone metabolism by mouse adrenal tissue were 5beta-reduced steroids. Differences were observed between LACA and NH strains of mice in that there was a lower metabolism of androstenedione by NH mouse adrenal and a considerable difference in the proportions of aetiocholanolone and epiaetiocholanolone produced. (+info)