INVITRO METABOLISM OF [H-3] 2,6-DINITROTOLUENE BY HUMAN AND RAT-LIVER

Liver slice tissue culture was used to compare human and rat liver metabolism of 2,6-dinitrotoluene (2,6-DNT). Oxidative metabolism of the 2,6-DNT side-chain methyl moiety produced 2,6-dinitrobenzylalcohol and the glucuronide conjugate of 2,6-dinitrobenzylalcohol, and reductive metabolism of the 2,6-DNT nitro groups produced 2-amino-6-nitrotoluene. Metabolites derived from side-chain oxidation accounted for 90-95% of the 2,6-DNT metabolites produced by rat liver slices under ambient oxygen concentrations of 25-100%; however, under 0% oxygen (100% nitrogen) atmospheres 2-amino-6-nitrotoluene accounted for 96% of the total metabolites. An increase in slice thickness from 0.3 to 0.8 mm decreased the ratio of oxidized to reduced 2,6-DNT metabolites produced by rat liver from 9:1 to 1:1. Under 100% oxygen and in liver slices approximately 0.3 mm thick, average rates of 2,6-DNT oxidative metabolism by human (five subjects) and rat liver were 1.0 and 2.1 nmol/min/g liver, respectively. K(m) and V(max) for the oxidative metabolism of 2,6-DNT by rat liver slices were 0.38 mm and 12 nmol/min/g liver, respectively. The average K(m) and V(max) for the oxidative metabolism of 2,6-DNT by two human subjects were 0.019 mm and 0.91 nmol/min/g liver, respectively.