Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole

The existence of a cytochrome P450-dependent 2,3-epoxide of the potent pneumotoxin 3-methylindole was indirectly confirmed using stable isotope techniques and mass spectrometry. Determination of hydride shift and incorporation of labeled oxygen in 3-methyloxindole and 3-hydroxy-3-methyloxindole, metabolites that may be in part dependent on the presence of the epoxide, were utilized as indicators of the epoxide's existence. One mechanism for the formation of 3-methyloxindole involves cytochrome P450-mediated epoxidation followed by ring opening requiring a hydride shift from C-2 to C-3. Through incubations of goat lung microsomes with [2-2H]-3-methylindole, the retention of 2H in 3-methyloxindole was found to be 81%, indicating a majority of the oxindole was produced by the mechanism described above. 3-Hydroxy-3-methylindolenine is an imine reactive intermediate that could be produced by ring opening of the 2,3-epoxide. The imine may be oxidized to 3-hydroxy-3-methyloxindole by the cytosolic enzyme aldehyde oxidase. Activities of this putative detoxification enzyme were determined in both hepatic and pulmonary tissues from goats, rats, mice, and rabbits, but the activities could not be correlated to the relative susceptibilities of the four species to 3-methylindole toxicity. The 18O incorporation into either 3-methyloxindole or 3-hydroxy-3-methyloxindole from both 18O2 and H218O was determined. The 18O incorporation into 3-methyloxindole from 18O2 was 91%, strongly implicating a mechanism requiring cytochrome P450-mediated oxygenation. Incorporation of 18O into 3-hydroxy-3-methyloxindole indicated that the alcohol oxygen originated from molecular oxygen, also implicating an epoxide precursor. These studies demonstrate the existence of two new reactive intermediates of 3-methylindole and describe the mechanisms of their formation and fate.     

Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.     

Heat-resistant thermoplastic/ chromic acid anodized Ti-6Al-4V single lap bond evaluation

Structural, heat-resistant thermoplastic adhesives were evaluated in single lap bonds. The amorphous thermoplastics tested were polyphenylquinoxaline, glass filled Ultem polyetherimide, unfilled Ultem polyetherimide, and Victerex polyethersulfone. The adherend was chromic acid anodized Ti-6Al-4V, tested unprimed and primed with Lica 44 titanate. Initial bond strengths were similar for all adhesives. In general, Lica 44 titanate primer did not affect bond strength. Bond strength was not influenced by 170°C ageing, but 232°C ageing did decrease bond strength when polyphenylquinoxaline was the adhesive. Failure occurred primarily in the adhesive fillet and propagated into the unprimed or primed anodic oxide/polymer interphase.     

Performance of a power conversion system for superconductingmagnetic energy storage (SMES)

This paper presents the results of laboratory tests of a power conversion system (PCS) for superconducting magnetic energy storage (SMES) applications. The PCS uses a two-quadrant chopper and a voltage-source power converter. Operating modes of the chopper are discussed. Operation of SMES to provide independent control of real and reactive power, operation as a static VAr compensator, low frequency modulation of the real power and speed of response are demonstrated. A circuit is presented for testing an SMES PCS that does not require a superconducting coil