Biomedical subjects
Publications and source records attributed to S Burstein.
When methanolic solutions of tritiated 11-deoxycorticosterone or corticosterone (0.1 to 300 ng) were evaporated to dryness with a stream of nitrogen in soda-lime test tubes only 8-24% of the radioactivity was recovered as the parent steroid. Evaporation in borosilicate test tubes led to a recovery of 90% or more. With ethyl acetate as solvent no decomposition occured in soda-lime test tubes.
The early kinetics of the conversion of cholesterol (A) to (22R)-22-hydroxycholesterol (B), (20R,22R)-20,22-dihydroxycholesterol (C) and pregnenolone (D) has been studied with bovine adrenocortical mitochondrial aceton-dried powder preparations. The sequential appearance of B, C, and D was demonstrated. During the lag period of D appearance, B, and C approached steady state levels, at which time the formation of D approximated linearity. The initial rate of B appearance approximated the rate of the linear phase of pregnenolone formation. When cholesterol was initially incubated in an 18O2-enriched atmosphere, the gas phase abruptly changed to air and incubation continued for a relatively short period, there was a drop in the 18O content of the recovered B and C. These results demonstrated for the first time the turnover of these compounds as they formed in the system from cholesterol, without the use of exogenously added tracer B or C. The 18O content of the recovered glycol was lower at position C-20 than at C-22, as would be expected from a consecutive process involving an initial oxygen attack of cholesterol at C-22. These results suggest the sequence A leads to B leads to C leads to D as the basic mechanism for the conversion of cholesterol to pregnenolone.
Cyclic AMP levels in primary monolayer cultures of epithelial cells prepared from mid-pregnant mice are stimulated by prostaglandin E1 and E2. Prostaglandin F1alpha and F2alpha have only a slight effect upon cyclic AMP levels. In the absence of phosphodiesterase inhibitors the rise in cyclic AMP produced by PGE1 is only transient and the levels return to normal within 30 minutes. High concentrations (16 mM) of theophylline are needed to prevent this decline, suggesting that the phosphodiesterase activity of epithelial cells in culture is high. However, theophylline alone produced only a small increase in basal cyclic AMP levels even over a 2-hour period indicating that basal cyclic AMP is turned over more slowly than cyclic AMP produced in response to stimulation with PGE1. Both PGE and PGF synthesis were monitored using radioimmunoassay procedures previously reported. The observed levels were found to decrease as cell density increased and were sensitive to the addition of agents such as collagen and naproxen.
Incubation of (22R)-(22-180)20-hydroxycholesterol with a bovine adrenocortical mitochondrial acetone-dried powder preparation in air yielded (20R, 22R)-20, (22-18O)22-dihydroxy-cholesterol. Incubation of (20S)-(20-18O)22-hydroxycholesterol yielded (20R, 22R)-(20-18O)20,22-dihydroxycholesterol. The formed glycols and the substrates reisolated at the end of the incubations had the same 18O abundance as the starting materials. No significant (20R, 22R)-20,22-dihydroxycholesterol was formed following incubation with either (E)-or (Z)-20, (22)-dehydrocholesterol. (20R,22S)-20, 22-Epoxycholesterol yielded approximately 1/5 of the amount of pregnenolone obtained in a similar incubation with cholesterol. No significant pregnenolone formation was observed with (20R, 22R)-20,22-epoxycholesterol. These results exclude a mechanism for the biosynthesis of (20R, 22R)-20,22-dihydroxycholesterol from the monohydroxylated cholesterol derivatives by way of dehydration followed by epoxidation and hydration. Similarly, the participation of an olefin and an epoxide as intermediates in the transformation of cholesterol to pregnenolone in acetone-dried powder preparations of adrenal cortex mitochondria is unlikely.
Incubation of cholesterol with a bovine adrenocortical mitochondrial acetone-dried powder preparation yielded (22R)-22-hydroxycholesterol (I), (20R,22R)-20,22-dihydroxycholesterol(II), and pregnenolone (III) which were conclusively identified by combined gas chromatography-mass spectrometry. Incubations with [4-14C]cholesterol yielded I, II, and III with specific activities (determined from partial mass-spectral scans) not significantly different from those of the used substrate or the cholesterol reisolated after the incubation, demonstrating that the isolated compounds arose mostly, if not entirely, from the substrate cholesterol. Incubations in an 18O-enriched atmosphere yielded I, II, and III with 18O at position C-22, C-20 and C-22, and C-20, respectively, providing evidence that the hydroxyl groups of the side chain of I and II and the C-20 oxygen atom of III originated from molecular oxygen. The distribution of the oxygen atoms in II after incubation with 18O2 and 16O2 (devoid of 16O18O) proved that the hydroxyl groups of the side chain of II were introduced from two different molecules of oxygen, consistent with a sequential hydroxylation of cholesterol. No (20S)-20-hydroxycholesterol was found. Incubation of I in an 18O-enriched atmosphere afforded II and III with 18O at C-20.
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The in vivo transformations of cannabinol (CBN) in the mouse have been studied and a pattern of metabolism established. As with other cannabinoids, the 7 position and the side chain are hydroxylated followed by further oxidation to acidic metabolites. Two of these CBN metabolites have been isolated previously as metabolites of delta1-tetrahydrocannabinol (THC) suggesting that CBN may be a transformation product of delta1-THC.
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Two of the major metabolites which appear in rabbit urine after the administration of Delta(1)-tetrahydrocannabinol have been isolated and their structures have been tentatively established. The available evidence indicates that they are 7-carboxy-Delta(1)-tetrahydrocannabinols with an additional hydroxyl group on the side chain. The substances occur both free and as conjugates.