Chiral inversion and stereoselective glutathione conjugation of the four 2-bromo-3-methylvaleric acid stereoisomers in the rat in vivo and in vitro.

Glutathione conjugation of the four 2-bromo-3-methylvaleric acid (BMV) stereoisomers was studied in vitro (rat liver cytosol) and in the rat in vivo (by monitoring biliary excretion of the glutathione conjugates). Rat liver cytosol catalyzed the formation of the corresponding glutathione conjugates in a ratio of 28:7:1:0 for the isomers 2S,3S-, 2S,3R-, 2R,3R- and 2R,3S-BMV, respectively. In the rat in vivo, a similar rank order was found: no conjugation of the 2R,3S isomer, whereas the biliary excretion half-lives of the GSH conjugates of the 2S,3S-, 2S,3R- and 2R,3R-isomers were 11, 36 and 70 min, respectively. These results show that isomers with the C2 carbon in the S configuration are more rapidly conjugated than those with the R configuration, and that the chiral center at the C3 carbon atom affects the conjugation rate at the C2 carbon. In addition to the SN2-type glutathione conjugates, from three substrates the glutathione conjugate of the corresponding diastereomer was formed, indicating bidirectional chiral inversion at the C2 carbon atom of the isomer. For instance, 2S,3R-BMV yielded both 2R,3R-MV-G and 2S,3R-MV-G. The biliary excretion half-lives of the "inverted" conjugates formed from the 2R,3S-, 2R,3R- and 2S,3R-isomer were 54 +/- 3, 75 +/- 3 and 38 +/- 3 min, respectively.