Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6.
Metabolic activities toward endogenous substrates in the brain, progesterone and p-tyramine, by cytochrome P450 2D6.2 (CYP2D6.2), CYP2D6.10A, CYP2D6.10C, and P34S, G42R, R296C, and S486T mutants expressed in recombinant Saccharomyces cerevisiae were compared with those by CYP2D6.1 (wild-type) in order to clarify the effects of genetic polymorphism of CYP2D6 on the metabolism of neuroactive steroids and amines in the brain. For the 6beta-hydroxylation of progesterone, the V(max) values for CYP2D6.2, CYP2D6.10A, and the P34S and G42R mutants, were less than half of those for CYP2D6.1, and CYP2D6.10C had a higher K(m) and a lower V(max) than the wild-type. The V(max)/K(m) values for CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were 12-31% of that for CYP2D6. The 16alpha-hydroxylation and 21-hydroxylation of progesterone by CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were not detected, and the R296C mutant had a higher K(m) for the 16alpha-hydroxylation and a lower V(max) for the 21-hydroxylation than those for CYP2D6.1. For dopamine formation from p-tyramine, the K(m) values for CYP2D6.2 and the R296C mutant were higher than those for CYP2D6.1, CYP2D6.10A, and CYP2D6.10C had a higher K(m) and a lower V(max) than the wild-type. The V(max)/K(m) values for CYP2D6.2, CYP2D6.10A, CYP2D6.10C and the P34S, G42R and R296C mutants were less than 45% of those for the wild-type. These results suggest the possibility that the polymorphism of CYP2D6, including CYP2D6*2, CYP2D6*10 and CYP2D6*12, might affect an individual behavior and the central nervous system through endogenous compounds, such as neuroactive steroids and tyramine, in the brain.
Department of Chemical Biology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Toshiro
T
Niwa
Toyoko
T
Hiroi
Daisuke
D
Tsuzuki
Shigeo
S
Yamamoto
Shizuo
S
Narimatsu
Tsuyoshi
T
Fukuda
Junichi
J
Azuma
Yoshihiko
Y
Funae
D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011110:Polymorphism, Genetic; D011374:Progesterone / Q000378:metabolism*; D014439:Tyramine / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D011374:Progesterone; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D004298:Dopamine; D014439:Tyramine