5-Hydroxytryptamine is biotransformed by CYP2C9, 2C19 and 2B6 to hydroxylamine, which is converted into nitric oxide

There is circumstantial evidence suggesting that 5-hydroxytryptamine (5-HT) could be biotransformed by enzymatic systems other than monoamino oxidase A, and that the isoforms of cytochrome P450 may be a source of nitric oxide. This study aimed to assess whether cytochrome P450 contributes to 5-HT biotransformation, and to provide evidence that 5-HT metabolism generates nitric oxide. Addition of 5-HT to cultured hepatocytes yielded 5-hydroxyindol acetic acid, a formation modulated by cytochrome P450 enzyme inducers and inhibitors. Recombinant human CYP2B6, 2C9 and 2C19 biotransformed 5-HT in 5-hydroxyindol acetic acid, but not CYP1A2, 2D6 or 3A4. Cultured hepatocytes with 5-HT generated nitric oxide, the amount of which was altered by cytochrome P450 enzyme inducers and inhibitors. In the presence of CYP2B6, 2C9 and 2C19, 5-HT relaxed precontracted isolated aortic rings, with or without endothelium, an effect prevented by the addition of methylene blue and an inhibitor of catalase, but not by myoglobin. In the absence of catalase, hydroxylamine was always assayed as a byproduct of 5-HT metabolism. In conclusion, CYP2B6, 2C9 and 2C19 biotransform 5-HT, yielding hydroxylamine, which is converted to nitric oxide in the presence of catalase. British Journal of Pharmacology (2004) 141, 407-414. doi:10.1038/sj.bjp.0705632