scholarly journals Metabolism of hydroanthracenones in rabbits

1972 ◽  
Vol 127 (1) ◽  
pp. 119-123 ◽  
Author(s):  
J. S. Robertson ◽  
P. J. Dunstan
Keyword(s):  
Aromatic Aldehyde ◽  
Carbonyl Compounds ◽  
Liver Alcohol Dehydrogenase ◽  
Enzyme Systems ◽  
Oxo Compounds ◽  
Successful Reduction ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

1. The metabolism of 1-oxo-octahydro- and 2- and 9-oxoperhydro-anthracenes was investigated in rabbits. All compounds increased the urinary glucuronide content. 2. The 1-oxo and 2-oxo compounds were reduced to the corresponding alcohols whereas the 9-oxo compound was hydroxylated. 3. The reduction in vitro of these compounds and related ketones was investigated with three different enzyme systems (liver alcohol dehydrogenase, hydroxy steroid dehydrogenase, aromatic aldehyde–ketone reductase) in an attempt to explain the results in vivo. 4. Successful reduction of many ketones with aromatic aldehyde–ketone reductase suggests that the kidney may be of importance in the reduction in vivo of certain cyclic carbonyl compounds.

scholarly journals Metabolism of 11-oxygenated steroids. Metabolism in vitro by preparations of liver

1968 ◽  
Vol 107 (2) ◽  
pp. 239-258 ◽  
Author(s):  
I. E. Bush ◽  
Sheila A. Hunter ◽  
R. A. Meigs
Keyword(s):  
Guinea Pig ◽  
Dehydrogenase Activity ◽  
Liver Microsomes ◽  
Competitive Inhibitor ◽  
Partial Purification ◽  
Substrate Complex ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

1. The isolation and partial purification of 11β-hydroxy steroid dehydrogenase from rat and guinea-pig liver microsomes has been achieved by conventional methods. 2. The efficiency of different 11-oxygenated steroids as substrates has been examined. The relative efficiencies confirm in the main the stereochemical theory of the enzyme–coenzyme–substrate complex that was proposed earlier on the basis of studies in vivo. Δ4-3-Ketones and 5α-hydrogen steroids are readily metabolized by the enzyme. 5β-Hydrogen steroids and Δ4-3-ketones with certain large α-substituents are metabolized to a limited extent or not at all. Halogen substitution in the 9α-position enhances the rate of reduction of 11-ketones but blocks the oxidation of the related 11β-ols. 3. 9α-Fluorocortisol is a competitive inhibitor of the oxidation of cortisol, but 9α-fluorocortisone is reduced at five to ten times the initial velocity of cortisone. 4. 11β-Hydroxy steroid dehydrogenase activity has been found in liver microsomes of rat, guinea pig, rabbit and calf. 5. Relative substrate efficiencies and Km values are similar in whole (debris-free) homogenates, washed microsomes and acetone-dried powders of washed microsomes. 6. A variety of conditions have been examined for the observation of 11β-hydroxy steroid dehydrogenase activity. NADP(H) is an efficient and NAD(H) a very poor coenzyme for the reaction.

scholarly journals Hormonal control of Luteal 20α-Hydroxy steroid dehydrogenase and Δ5-3β-hydroxy steroid dehydrogenase during luteolysis in the pregnant rat

1975 ◽  
Vol 152 (3) ◽  
pp. 433-443 ◽  
Author(s):  
R G Rodway ◽  
N J Kuhn
Keyword(s):  
Prostaglandin F2α ◽  
Late Pregnancy ◽  
Normal Pregnancy ◽  
Hormonal Control ◽  
Placental Lactogen ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

Treatment of pregnant rats with human chorionic gonadotrophin, luteotrophin (luteinizing hormone), luteotrophin-releasing hormone, prostaglandin F2α, aminoglutethimide, or by foetoplacental removal or hysterectomy achieved a common multiple-response pattern, namely increased activity of luteal 20α-hydroxy steroid dehydrogenase with decreased activity of delta5-3β-hydroxy steriod dehydrogenase and release of delta4-3-oxo steroids in vitro. 2. Similar effects of foetoplacental removal are noted in pregnant mice. 3. Gonadotrophin induced lower activities of 20α-hydroxy steroid dehydrogenase, except at the very end of pregnancy, and partly inhibited the induction caused by foetoplacental removal. 4. The results suggest that existence of a placental factor that restrains these changes until the end of normal pregnancy, which is produced in amounts proportional to the number of placentae and is conveyed to the ovary via the blood. 5. This factor was not replaced by prolactin. 6. It is argued that neither placental lactogen nor pituitary luteotrophin participate in the induction of 20α-hydroxy steroid dehydrogenase at late pregnancy in the rat. 7. Aminoglutethimide induced 20α-hydroxy steroid dehydrogenase only in late pregnancy. This was partly reversed by progesterone, wholly reversed by progesterone plus oestrogen, and did not involve the pituitary.

Cholinesterase Inhibition by Potato Glycoalkaloids Slows Mivacurium Metabolism

2000 ◽  
Vol 93 (2) ◽  
pp. 510-519 ◽  
Author(s):  
Daniel S. McGehee ◽  
Matthew D. Krasowski ◽  
Dennis L. Fung ◽  
Barry Wilson ◽  
Gerald A. Gronert ◽  
...  
Keyword(s):  
Cholinesterase Inhibitors ◽  
Neuromuscular Blocking ◽  
Dietary Factors ◽  
Serum Cholinesterase ◽  
Cholinesterase Inhibition ◽  
Duration Of Action ◽  
Neuromuscular Blocking Drugs ◽  
Enzyme Systems

Background The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), alpha-solanine and alpha-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro. Methods Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis. Results SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30-100 nm) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 +/- 12% of control; n = 12). Conclusions These findings support the hypothesis that inhibition of endogenous enzyme systems by dietary factors can influence anesthetic drug metabolism and duration of action. Diet may contribute to the wide variation in recovery time from neuromuscular blockade seen in normal, healthy individuals.

Extrarenal production and activation of human plasma prorenin: the evidence after venous occlusion

1989 ◽  
Vol 67 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Gregory M. T. Hare ◽  
Arlene Y. Loh ◽  
Daniel H. Osmond
Keyword(s):  
Human Plasma ◽  
Venous Occlusion ◽  
Local Activation ◽  
Active Renin ◽  
Inhibitory Capacity ◽  
Enzyme Systems ◽  
Plasma Active Renin

Venous occlusion of the left arm in consenting men was induced for 10 or 20 min to stimulate local fibrinolytic and other proteases, thereby favouring the conversion of prorenin to renin. Using the two techniques cryoactivation and tryptic activation, we found that plasma active renin increased significantly after such occlusion (10 and 20 min) while prorenin rose more convincingly and progressively from 10 to 20 min. The renin increase can be partially attributed to hemoconcentration, but in vivo production and (or) local activation of prorenin to renin cannot be excluded. The prorenin rise can apparently be attributed to local extrarenal production, and not to hemoconcentration or influx, since it was progressive and neither prorenin nor renin levels were raised at all in blood circulating outside the occluded arm. Prekallikrein and plasminogen levels were elevated in occlusion plasmas, but responsibility of these enzyme systems for any enhanced activation of prorenin was not established. The trypsin inhibitory capacity was also elevated, increasing the requirement of trypsin to achieve optimal activation of prorenin, but not changing the prorenin estimate itself. Thus, prorenin appears to be released extrarenally, within the vasculature of an occluded arm, while in vitro evidence suggests that the mechanisms for its activation were stimulated. The importance of such extrarenal production and activation of prorenin for renin production under other physiological or pathophysiological conditions remains to be determined.Key words: venous occlusion, extrarenal prorenin, production, activation.

The effect of prenatal treatment with busulfan on in vitro androgen production by testes from rats of various ages

1985 ◽  
Vol 63 (9) ◽  
pp. 1155-1158 ◽  
Author(s):  
Gwenderlyn F. Jansz ◽  
David K. Pomerantz
Keyword(s):  
Leydig Cells ◽  
Testicular Tissue ◽  
Developmental Changes ◽  
Seminiferous Tubules ◽  
Apparent Paradox ◽  
Old Rats ◽  
Effect Of Treatment ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

Treatment of rats with busulfan in utero severely depletes the germ cell population of the seminiferous tubules. These studies have examined the in vitro capacity of testicular tissue and Leydig cells from such testes to secrete androgens. Leydig cells were identified by staining for 3β-hydroxy steroid dehydrogenase. Rats were studied at several ages to identify any developmental changes in the androgen-secreting capacity of control and treated gonads. At 30 days of age, no effect of treatment on serum androgen was found. At 60 and 90 days of age, treatment caused decreased androgen and increased LH content of the serum. At 12, 30, 60, and 90 days of age, the amount of androgen secreted per milligram of testicular tissue in response to LH was higher in busulfan-treated rats. Leydig cells from 60- and 90-day-old rats which had received busulfan were also hyperresponsive to LH. It was concluded that Leydig cells from testes essentially devoid of germ cells were hyperresponsive to LH. Serum androgen levels were decreased yet androgen production per Leydig cell was increased. A possible explanation of this apparent paradox is that busulfan treatment resulted in decreased numbers of Leydig cells in the gonads.

Acetazolamide and renal ammoniagenesis

1978 ◽  
Vol 234 (3) ◽  
pp. F235-F237 ◽  
Author(s):  
S. K. Chapman ◽  
M. S. Hoover
Keyword(s):  
Ammonium Excretion ◽  
Gamma Glutamyl Transpeptidase ◽  
Gamma Glutamyl ◽  
Enzyme Systems ◽  
Glutamyl Transpeptidase

The effect of acetazolamide on ammonia-producing enzyme systems was determined in vitro at concentrations comparable to those which have been shown to abolish ammonium excretion in vivo. No change in the activity of glutaminase or gamma-glutamyl transpeptidase could be observed at concentrations up to 0.2 mM acetazolamide, and concentrations up to 1 mM were without effect on D-glutamyltransferase activity. Therefore, the effect of acetazolamide to abolish ammonium excretion cannot be explained by an action of the drug to inhibit ammoniagenesis.

EFFECT OF CLOMIPHENE ON AROMATIZATION OF STEROIDS BY THE HUMAN PLACENTA IN VITRO

1963 ◽  
Vol 44 (4) ◽  
pp. 519-528 ◽  
Author(s):  
Olive W. Smith ◽  
Caroline F. Day
Keyword(s):  
Human Placenta ◽  
Average Increase ◽  
Enzyme Systems ◽  
Per Se ◽  
Human Ovaries

ABSTRACT Results of in vivo experiments in women (Smith et al. 1963) have raised the possibility that clomiphene per se may be capable of stimulating one or more of the enzyme systems involved in ovarian biosynthesis of oestrogens. In the in vitro experiments herein reported, the effect of adding this drug to a preparation of human placenta capable of converting certain C19 steroids to ring A phenols was investigated. The substrates were inert and radioactive testosterone and androstenedione. In each of 6 experiments involving, besides the controls, nine direct comparisons between the yields of oestrone with versus without clomiphene added, there was clear evidence that the addition of clomiphene increased the rate of this reaction. The conversion of radioactive precursors was increased by an average of 23.4%. Measured chemically, in the same experiments, the average increase was 27.0%. That the results reported are related to the stimulatory effect of this drug upon steroidogenesis in human ovaries remains to be proven.

scholarly journals Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1148
Author(s):  
Tarek A. Ahmed ◽  
Khalid M. El-Say ◽  
Fathy I. Abd-Allah ◽  
Abdelsattar M. Omar ◽  
Moustafa E. El-Araby ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Binary System ◽  
Aromatic Aldehyde ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Oral Drug ◽  
Cell Disease ◽  
Sprague Dawley

Background: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O2-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O2-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. Methods: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-β-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-β-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. Results: Aqueous solubility of PP10 was enhanced ~5 times with the HP-β-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. Conclusion: Oral and IV formulations of PP10 were successfully developed using HP-β-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability.

INHIBITION OF PLACENTAL 3β-HYDROXY-STEROID DEHYDROGENASE BY NATURALLY OCCURRING STEROIDS. A POTENTIAL MECHANISM REGULATING OESTROGEN SYNTHESIS FROM UNCONJUGATED PRECURSORS

1975 ◽  
Vol 79 (4) ◽  
pp. 740-748 ◽  
Author(s):  
John D. Townsley
Keyword(s):  
Regulatory Mechanism ◽  
Initial Rate ◽  
Inhibitory Effects ◽  
Alternative Substrates ◽  
Naturally Occurring ◽  
Potential Inhibitors ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase ◽  
Endogenous Steroids

ABSTRACT We have proposed that inhibition of placental steroid 3-sulphatase by endogenous steroids may regulate oestrogen synthesis during human pregnancy. The possibility that an additional regulatory mechanism, involving the placental 3β-hydroxy-steroid dehydrogenase (SDH), may also be operative has now been examined. Inhibitory effects of naturally occurring steroids on SDH activity were determined from the reduction in initial rate of conversion of 3H-dehydroepiandrosterone to non-digitonin precipitable products by 10 000 × g supernatant from homogenates of human term placentae. The apparent Km for dehydroepiandrosterone was 0.33 × 10−6 m. Δ4-3-Oxo products of SDH action (4-androstene-3,17-dione, app. Ki = 0.60 × 10−6 m; progesterone, app. Ki = 1.5 × 10−6 m) were the most potent inhibitors and appeared to act non-competitively. Δ5-3β-Hydroxy alternative substrates were less inhibitory and in the case of pregnenolone (app. Ki = 4.5 × 10−6 m) behaved competitively. 11β-, 16α-, 17α- or 21-hydroxylation and epimerization of 3β- or 17β-hydroxyl functions of inhibitors decreased their activity. It is concluded that inhibition of both sulphatase and SDH by endogenous steroids may provide complementary methods of regulating placental oestrogen synthesis in vivo. The SDH mechanism may regulate oestrogen synthesis from unconjugated precursors, either formed within the placenta or derived from the circulation. The major potential inhibitors appear to be Δ4-3-ketones, acting non-competitively, and formed within the placenta. In the sulphatase mechanism alternative substrates of extraplacenta origin, acting competitively, are the major potential inhibitors controlling utilization of conjugated precursors.

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