Interspecies comparison in the COMT-mediated methylation of 3-BTD

Abstract

Catechol-O-methyltransferase (COMT) is a druggable biological target and COMT modulators have been widely applied in the treatment of various central and peripheral nervous system disorders. The interspecies differences of COMT were carefully investigated using 3-BTD (a newly developed fluorescent probe of COMT) methylation as the probe reaction, and liver S9 from humans and seven experimental animals including monkeys, dogs, mice, rats, minipigs, guinea pigs and New Zealand rabbits as the enzyme source. Metabolite profiling demonstrated that all the tested liver S9 samples from the different animals could catalyse 3-BTD methylation but displayed significant differences in reaction rate. Also, the differential effects of tolcapone (a potent inhibitor against COMT) on 3-BTD methylation among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (Cl_int) for 3-BTD methylation in liver S9 from the different animals were determined, and the order of the Cl_int values for the formation of 3-BTD was RLS9 > DLS9 ≈ PLS9 > MLS9 > CyLS9 > RaLS9 > GpLS9 > HLS9. These findings are helpful for further exploring COMT-associated biological processes in animal models, as well as for developing therapeutic molecules that target COMT.