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Much evidence supports the view that the rate of conjugation of glutathione (GSH) with aflatoxin B1 (AFB1) exo-epoxide is an important factor in determining the species variation in risk to aflatoxins and that induction of GSH S-transferases can yield a significant protective effect. An assay has been developed in which the enzymatic formation of the conjugates of GSH and AFB1 exo-epoxide and the recently described AFB1 endo-epoxide is measured directly. 1H NMR spectra are reported for both the AFB1 exo- and endo-epoxide-GSH conjugates. Structural assignments were made by comparison with AFB1 exo- and endo-epoxide-ethanethiol conjugates, for which nuclear Overhauser effects were measured to establish relative configurations. The endo-epoxide was found to be a good substrate for GSH conjugate formation in rat liver cytosol while mouse liver cytosol conjugated the exo-epoxide almost exclusively. Human liver cytosol conjugated both epoxide isomers to much lower extents than did cytosols prepared from rats or mice. Purified rat GSH S-transferases catalyzed the formation of the AFB1 exo-epoxide-GSH conjugate in the order 1-1 approximately 4-4 approximately 3-3 greater than 2-2 greater than 4-6 (7-7 and 8-8 did not form the exo-epoxide-GSH conjugate at levels above the nonenzymatic rate). The only rat GSH S-transferases that conjugated the endo-epoxide were 4-4 and 4-6, with 4-4 being the more active.(ABSTRACT TRUNCATED AT 250 WORDS)
The (+)-,(-)-, and (+/-)-2H5-methadones, which contained five deuterium atoms in one aromatic ring, were synthesized for use in clinical pharmacological studies and as internal standards. GLC-chemical-ionization mass spectrometry was used to determine plasma and urinary methadone levels by an inverse isotope dilution assay. Plasma drug levels could be determined to 10 pmoles/ml, and urine levels could be measured to 5 pmoles/ml. Plasma methadone levels were examined in several patients undergoing methadone maintenance therapy. These levels generally ranged between 100 and 400 ng/ml (320-1300 pmoles/ml) after an average oral dose of 1 mg/kg/day. The methadone half-life was 28.8 +/- 4.8 hr.