Phthalate esters enhance quinolinate production by inhibiting amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), a key enzyme of the tryptophan-niacin pathway

We investigated the effects of dietary phthalic acid diesters (PAEs) on the metabolism of Trp-niacin in rats. The administration of PAEs increased the formation of Trp metabolites beyond QA such as nicotinamide and N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and N1-methyl-4-pyridone-3-carboxamide. In other words, the intake of PAEs gave the increase in the conversion ratio of Trp to niacin. Then, we investigated the effects of dietary PAEs on major enzyme activities involved in the metabolism of Trp-niacin. Based on the findings that the formation of QA and its metabolites significantly increased with PAEs administration, we proposed that the activity of ACMSD (EC 4.1.1.45) would be inhibited by PAEs intake. However, we did not find that the activity decreased in the rats fed with PAEs containing diet. To assess the effects of various PAEs on the metabolites of the Trp-niacin pathway, rats were fed with a diet containing dimethylphthalate, diethylphthalate, di-n-butylphthalate, di-n-octyl phthalate, and di-2-ethylhexylphtahlate (DEHP). The results showed that the length and structure of side chains in the esters appeared to be crucial for the formation of Trp metabolites. DEHP that has long and branched side chains was the most powerful disruptor of Trp metabolism. Because the PAE-induced effects may be due to the monoesters that are produced in the digestive organs, we also examined phthalate monoesters. Rats were fed with a diet containing mono-n-butylphthalate, mono-n-hexylphthalate, mono-2-ethylhexylphthalate (MEHP). The results were very similar to those when the diesters were used. There is the possibility that direct effect of DEHP and MEHP on the in vitro activity of ACMSD and QPRT were tested. Although DEHP could not be tested because of its low solubility, MEHP reversibly inhibited ACMSD. In contrast, neither QPRT was affected by any of the phthalate monoesters. Correlation between inhibition of ACMSD by PAEs with different side chains and the formation of QA supports the notion that PAEs perturb Trp metabolism by inhibiting ACMSD.