Cellular and subcellular studies of the biotransformation of hexamethylmelamine in rat isolated hepatocytes and intestinal epithelial cells.

The antitumor agent hexamethylmelamine is subject to oxidative metabolic conversion in rat isolated liver and small intestinal cells (conversion 40 times higher in hepatocytes). This N-demethylation is mediated by cytochrome P-450 in the microsomal fractions, and in mitochondrial preparations it has been found to occur via N- methylolpentamethylmelamine . Somehow, pentamethylmelamine, hydroxymethylpentamethylmelamine , or an intermediary metabolite becomes trapped in the intact cell, but the nature of the adduct formed is still unresolved. Pretreatment of rats with 3-methylcholanthrene p.o. caused a 5-fold increase in hexamethylmelamine turnover. Phorone administered in vivo prior to cell preparation (liver and gut) caused an increase in pentamethylmelamine production. The latter results together with results of adding glutathione to cell incubations demonstrate that glutathione contributes to the regulation of cytochrome P-450-mediated N-demethylation of hexamethylmelamine.