The fact that CYP2D6 is not only expressed in liver but also in brain and the clinical association of this cytochrome with Parkinson's disease suggests the possibility of existence of some endogenous substrate, and among these perhaps one or more neurotransmitters could be metabolized by CYP2D6. In this study we explored such a possibility by studying the modulation of CYP2D6 activity by several neurotransmitters. Our findings confirm the occurrence of a competitive inhibition of dextromethorphan O-demethylation in the presence of tryptamine, with a Ki value of 44.6 microM. Tryptamine was metabolized in human liver microsomes by an enzyme activity with a K(m) of 3.6 +/- 0.9 microM. Such activity is NADPH dependent and is inhibited by quinidine and CYP2D6-specific substrates. The product of the reaction is tryptophol. These results suggest that tryptamine may be an endogenous substrate of CYP2D6.