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.
Niwa
Toshiro
T
Department of Chemical Biology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Hiroi
Toyoko
T
Tsuzuki
Daisuke
D
Yamamoto
Shigeo
S
Narimatsu
Shizuo
S
Fukuda
Tsuyoshi
T
Azuma
Junichi
J
Funae
Yoshihiko
Y
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