Mechanism of methylphosphonic acid photo-degradation based on phosphate oxygen isotopes and density functional theory.

Methylphosphonic acid (MPn) is an intermediate in the synthesis of the phosphorus-containing nerve agents, such as sarin and VX, and a biosynthesis product of marine microbes with ramifications to global climate change and eutrophication. Here, we applied the multi-labeled water isotope probing (MLWIP) approach to investigate the C-P bond cleavage mechanism of MPn under UV irradiation and density functional theory (DFT) to simulate the photo-oxidation reaction process involving reactive oxygen species (ROS). The results contrasted with those of the addition of the ROS-quenching compounds, 2-propanol and NaN3. The degradation kinetics results indicated that the extent of MPn degradation was more under alkaline conditions and that the degradation process was more rapid at the initial stage of the reaction. The phosphate oxygen isotope data confirmed that one exogenous oxygen atom was incorporated into the product orthophosphate (PO4) following the C-P bond cleavage, and the oxygen isotopic composition of this free PO4 was found to vary with pH. The combined results of the ROS-quenching experiments and DFT indicate that the C-P bond was cleaved by OH-/˙OH and not by other reactive oxygen species. Based on these results, we have established a mechanistic model for the photolysis of MPn, which provides new insights into the fate of MPn and other phosphonate/organophosphate compounds in the environment.

Oxygen isotope ratios of PO4: an inorganic indicator of enzymatic activity and P metabolism and a new biomarker in the search for life.

The distinctive relations between biological activity and isotopic effect recorded in biomarkers (e.g., carbon and sulfur isotope ratios) have allowed scientists to suggest that life originated on this planet nearly 3.8 billion years ago. The existence of life on other planets may be similarly identified by geochemical biomarkers, including the oxygen isotope ratio of phosphate (delta(18)O(p)) presented here. At low near-surface temperatures, the exchange of oxygen isotopes between phosphate and water requires enzymatic catalysis. Because enzymes are indicative of cellular activity, the demonstration of enzyme-catalyzed PO(4)-H(2)O exchange is indicative of the presence of life. Results of laboratory experiments are presented that clearly show that delta(18)O(P) values of inorganic phosphate can be used to detect enzymatic activity and microbial metabolism of phosphate. Applications of delta(18)O(p) as a biomarker are presented for two Earth environments relevant to the search for extraterrestrial life: a shallow groundwater reservoir and a marine hydrothermal vent system. With the development of in situ analytical techniques and future planned sample return strategies, delta(18)O(p) may provide an important biosignature of the presence of life in extraterrestrial systems such as that on Mars.

The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone.

OBJECTIVES: To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. DESIGN: Prospective, randomized, open label crossover protocol with 7 days between dosages. SETTING: Academic institution. PARTICIPANTS: Fifteen normal postmenopausal women. INTERVENTIONS: All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. MAIN OUTCOME MEASURES: Serum P concentrations were measured in all groups. RESULTS: Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. CONCLUSIONS: Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.

Dexamethasone suppresses sex-hormone binding globulin.

Dexamethasone suppression (DEX-S) for 14 days has been used to determine the probable source of androgen excess. The exact mechanism(s) of DEX-S is still unclear. The authors postulated that dexamethasone (DEX) inhibits either the synthesis or secretion of sex-hormone binding globulin (SHBG). To examine this hypothesis, 14 women with polycystic ovarian disease (PCOD) and 3 volunteers were given DEX for 14 days. The PCOD group included obese and nonobese women (+/- 15% ideal body weight). Plasma determinations by radioimmunoassay of total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate, luteinizing hormone; follicle-stimulating hormone; cortisol, and SHBG were made. DEX suppressed SHBG levels (P less than 0.01). SHBG levels were significantly lower in the obese than in the nonobese (P less than 0.01). All androgens were suppressed by DEX, with the exception of androstenedione post-DEX levels, which were significantly greater than pre-DEX levels in 6 of 14 subjects (P greater than 0.05). This observation is consistent with DEX suppression of SHBG.

Prolactinoma and adrenal androgens.

Theories about the relationship between hyperprolactinemia and hyperandrogenism are conflicting. Several reports assert that prolactin affects the delta 5 and delta 4 pathways through its effect on the activity of 3beta-hydroxysteroid dehydrogenase (3beta-OHSD). We measured delta 5 and delta 4 steroids, prolactin and cortisol in 18 amenorrheic, hyperprolactinemic women before and after resection of prolactinomas. Similar determinations of delta 5: delta 4 steroids were made in a control group of five women. The ratios of individual delta 5: delta 4 steroids were also analyzed. Our results support a modification of delta 5, delta 4 pathways through an effect on the rate-limiting enzyme 3 beta-OHSD. In hyperprolactinemic women the differences between the preoperative and postoperative steroid levels were significant. Further, since the androgens decreased irrespective of the prolactin following surgery, there probably is a factor other than ACTH and prolactin modulating the adrenal androgens.