Enzymatic S-methylation of 6- n-propyl-2-thiouracil and other antithyroid drugs

Abstract

Mouse kidney thiol transmethylase and S-adenosylmethionine were incubated with the radioactive antithyroid drugs, 2-thiouracil (TU), 6-propyl-2-thiouracil (PTU), methimazole (MMI). 6-methyl-2-thiouracil (6-methyl TU) or thiourea. Radioactive metabolites were produced with TU, PTU and 6-methyl TU and, in each case. were identified as the corresponding S-methyl derivatives. No measurable metabolism of MMI or thiourea was observed. Kinetic studies with the partially purified enzyme demonstrated K m values for TU, PTU and 6-methyl TU of 1 × 10 −3 M, 2.5 × 10 −3 M and 1.54 × 10 −3 M respectively. Extensive investigation with PTU demonstrated that methylation was to the sulfur rather than the nitrogen of the thiopyrimidine and that the pH optimum for PTU was 8.0. Methylation of PTU was proportional to enzyme concentration, with little spontaneous methylation occurring, and was not reversible. TU and 6-methyl TU inhibited PTU metabolism and were apparently competitive substrates. Thiouracil nucleoside and thiouracil nucleotide were not substrates for the enzyme. Studies with porcine thyroid peroxidase demonstrated that S-methylation of PTU. TU and MMI abolished the antiperoxidase activity observed with the parent compound. The results obtained demonstrate that S-methylation is a general pathway of metabolism for thiopyrimidine antithyroid drugs, but not for thiourea or MMI, which markedly decreases the antiperoxidase activity of the parent compound.