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Cellular and Subcellular Studies of the Biotransformation of Hexamethylmelamine in Rat Isolated Hepatocytes and Intestinal Epithelial Cells

Departments of Pharmacology and Pharmacotherapy [P. J. A. B., A. C. F-S., J. N.] and Analytical Pharmacy [M-J. J. M., A. H.], State University of Utrecht, Faculty of Pharmacy, Catharijnesingel 60, 3511 GH Utrecht, and Department of Veterinary Pharmacology, Pharmacy and Toxicology, State University of Utrecht, Biltstraat 172, Utrecht [M. van G.], The Netherlands

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 tumover. 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.

¹ To whom requests for reprints should be addressed.

Received 11/28/83. Accepted 3/30/84.