IDENTIFICATION OF GOAT AND MOUSE URINARY METABOLITES OF THE PNEUMOTOXIN, 3-METHYLINDOLE

1. Urine from goats dosed i.v. with 3-methylindole (3MI; 15 mg/kg) or [methyl-C-14] 3MI (15 mg/kg, 0.5 muCi/kg) contained at least 11 metabo lites of 3MI. 2. Goat metabolized 3MI to sulfate conjugates of 4- or 7 -hydroxy-3-methyloxindole, 5- or 6-hydroxy-3-methyloxindole, and 3,5- or 6-dihydroxy-3-methyloxindole; glucuronic acid conjugates of indole- 3-carboxylic acid and 4- or 7-hydroxy-3-methyl-oxindole; and unconjuga ted 3-hydroxy-3-methyloxindole. Diastereoisomeric glucuronic acid conj ugates of 3-hydroxy-3-methyloxindole were also identified in goat urin e. 3, Urine from mice dosed i.p. with 3MI (400 mg/kg) or [ring-UL-C-14 ] 3MI (400 mg/kg, 125 muCi/kg) contained at least six metabolites of 3 MI. 4. Mice metabolized 3MI to glucuronic acid conjugates of 3,5- or 6 -dihydroxy-3-methyloxindole, 5- or 6-hydroxy-3-methyloxindole, and ind ole-3-carboxylic acid; and unconjugated indole-3-carboxylic acid. Unco njugated 3-hydroxy-3-methyloxindole was identified in mouse urine in a previous report. 5. Both goats and mice metabolized 3MI to a mercaptu rate, 3-[(N-acetyl-L-cystein-S-yl)methyl]indole, which has been previo usly identified and was confirmed in this study. 6. 3-Methyloxindole w as not identified in the urine of either goats or mice. 7. The major p athways of 3MI biotransformation in goats and mice is the formation of mono- and dihydroxy-3-methyloxindoles and their subsequent conjugatio n with glucuronic acid or sulfate. 8. There are no apparent qualitativ e differences in the biotransformation of 3MI between goats and mice t hat can account for their different sensitivities to 3MI-induced lung injury.