The effects of high dietary levels of saccharine on in vivo and in vitro drug metabolism

High dietary levels of saccharin (≥3%) increase the incidence of bladder tumours in male rats when given during neonatal development and subsequently throughout life. The administration of high dietary levels of sodium saccharin to rats, is also associated with a number of biochemical and physiological changes which may influence tumour development, such as the accumulation of soluble protein and tryptophan in the caecum. The aim of the present study was to determine whether the biochemical changes associated with saccharin treatment, could affect the reactions involved in drug metabolism. Administration of a diet containing 7.5% saccharin did not affect the levels of liver cytochrome p450, cytochrome b5, NADPH cytochrome-P450-reductase, aryl hydrocarbon hydroxylase, N-acetyltransferase or glutathione, but caused a reversible increase in dimethylnitrosamine-N-demethylase activity. An intraperitoneal injection of [^14C]-phenol] was used as an in vivo probe to investigate the effect of saccharin on phase 2 conjugation pathways. High dietary levels of sodium saccharin caused a shift in the conjugation pattern of phenol. A decrease in the excretion of phenol-sulphate was found during neonatal development which was associated with an increase in the amounts of quinol-glucuronide recovered. The pattern of phenol-sulphate excretion was inversely related to the concentration of indican recovered in the urine of the saccharin treated rats. Incorporation of 5% cysteine into the diet of the saccharin treated animals prevented the observed alteration in conjugation pattern. This suggests that in the young rat, high dietary levels of saccharin cause both sulphate depletion and/or saturation of the sulfotransferase enzyme, at a time when the glucuronyltransferase enzymes are still immature. As study was also undertaken to determine whether the effect on sulphate conjugation could alter the conjugation pattern of an endogenous tryptophan metabolite, namely 3-hydroxyanthranilic acid. The results obtained showed that there was a decrease in the extent of sulphate conjugation of 3-hydroxyanthranilic acid in rats fed saccharin diet. Therefore saccharin may alter the pattern of conjugation of anutrients during neonatal development, indicating the presence of major biochemical abnormalities in animals subjected to tumourigenic dietary concentrations of saccharin. (DX86092)