Herbicide safeners (protectants, antidotes) are used to protect crop plants from herbicide injury. Currently our understanding of the mechanisms involved in the protection of plants by safeners is not well defined; therefore, investigations were conducted to elucidate the mechanism(s) of action of the oxime ether safeners. Molecular comparisons of selected herbicide-safener combinations using computer-aided molecular modeling revealed that the chemical structures of safeners and herbicides are very similar at the molecular level; and, indicate that these compounds could bind at the same active site of the target protein or they may serve as inducers of metabolic enzymes which detoxify herbicides. Metolachlor at 10 μM and seed-applied CGA-133205 had no effect on germination while treatment with seed-applied oxabetrinil significantly reduced germination of grain sorghum. Results from experiments on ¹⁴C-acetate incorporation into lipids indicate that metolachlor and the oxime ether safeners influence lipid metabolism causing a redistribution of carbon in the lipid fractions of germinating sorghum roots. Results from studies with acetyl-CoA carboxylase indicate that this enzyme is not a target site for either metolachlor or the oxime ether safeners. Metolachlor and the oxime ether safeners enhanced glutathione levels in grain sorghum seedlings at 12 to 48 hr after imbibition was initiated with oxabetrinil being more stimulatory than metolachlor or CGA-133205. Glutathione reductase activity was also stimulated in safener-treated grain sorghum seedlings. Both safeners slightly enhanced nonenzymatic and enzymatic conjugation of metolachlor with reduced glutathione. Oxabetrinil conjugated enzymatically or nonenzymatically with reduced glutathione at a slow rate, but CGA-133205 did not. These data suggest that during the early stages of seed germination and seedling development of grain sorghum, safeners can enhance the detoxication of metolachlor by enhancing glutathione levels and enzymatic and nonenzymatic conjugation of metolachlor with glutathione. It appears that oxabetrinil and CGA-133205 are conferring protection to grain sorghum by increasing the rate of metolachlor metabolism. / Ph. D.