Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamateby flavin monooxygenase in human renal microsomes

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol de terrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-die thylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Severa l isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) meta bolize MeDDC in the liver. The human kidney contains FMO1 and several isofo rms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subf amilies. In this study the metabolism of MeDDC by the human kidney was exam ined, and the enzymes responsible for this metabolism were determined. MeDD C was incubated with human renal microsomes from five donors or with insect microsomes containing human FMO1, CYP4A11, CYP3A4, CYP3A5, or CYP2B6. MeDD C sulfine was formed at 5 muM MeDDC by renal microsomes at a rate of 210 +/ - 50 pmol/min/mg of microsomal protein (mean +/- S.D., n = 5) and by FMO1 a t 7.6 +/- 0.2 nmol/min/nmol (n = 3). Oxidation of 5 muM MeDDC was negligibl e by all CYP450 tested (less than or equal to0.03 nmol/min/nmol). Inhibitio n of FMO by methimazole or heat diminished MeDDC sulfine formation 75 to 89 % in renal microsomes. Inhibition of CYP450 in renal microsomes by N-benzyl imidazole or antibody to the CYP450 NADPH reductase had no effect on MeDDC sulfine production. Benzydamine N-oxidation, a probe for FMO activity, corr elated with MeDDC sulfine formation in renal microsomes (r = 0.951, p = 0.0 13). The K-M values for MeDDC sulfine formation by renal microsomes and rec ombinant human FMO1 were 11 and 15 muM, respectively. These results demonst rate a role for the kidney and FMO1 in the metabolism of MeDDC in humans.