| Abstract: | 4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is metabolized by a hepatic microsomal enzyme system composed of rat liver microsomes, a reduced nicotinamide adenine dinucleotide phosphate-generating system, cytosolic protein (or glutathione), and oxygen. Omission of any one of the components, or incubation under an atmosphere of CO or N2, results in inhibition of the reaction. Also, the addition of inhibitors of microsomal metabolism (alpha-naphthoflavone, metyrapone, or SKF 525-A) decreases m-AMSA metabolism. Metabolism of m-AMSA is more rapid with microsomes prepared from rats pretreated with phenobarbital or 3-methylcholanthrene. Two microsomal oxidation products of m-AMSA were isolated and identified as N1'-methanesulfonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohex adiene-1', 4'-dimine (m-AQDI) and 3'-methoxy-4'-(9-acridinylamino-2',5'-cyclohexadien-1'-one (m-AQI). m-AQDI reacts with glutathione to form a product previously identified in in vivo studies as the principal rat biliary metabolite and which is not cytotoxic to cultured L1210 cells. Thus, the end result of the microsomal metabolism of m-AMSA is detoxification. However, the two primary oxidation products (m-AQDI and m-AQI) are considerably more cytotoxic to L1210 cells in vitro than is m-AMSA. The concentration of m-AMSA required to produce a 5-log kill is 1.0 microgram/ml compared to 0.01 microgram/ml for m-AQDI and m-AQI. These results indicate that m-AMSA might undergo bioactivation to form the active cytotoxic species of the drug. |
