PMID- 10064570
OWN - NLM
STAT- MEDLINE
DCOM- 19990407
LR  - 20131121
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 27
IP  - 3
DP  - 1999 Mar
TI  - G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese.
PG  - 385-8
AB  - The molecular basis of the reduced ability of a Chinese to metabolize
      debrisoquine was explored by sequencing all of the nine exons of the CYP2D6 gene.
      The subject has T188, A1846, T2938, and C4268 (CYP2D6*14) instead of C188, G1846,
      C2938, and G4268 as in wild-type subjects. XbaI restriction fragment length
      polymorphism indicated that the subject has a 29-kb allele and a gene deletion
      (11.5 kb) in another allele (CYP2D6*5). A CYP2D6*14 allele together with a
      CYP2D6*5 allele may cause the poor metabolism of the subject. T188, T2938, and
      C4268 are common haplotypes in Chinese-extensive metabolizers. The effect of
      G1846 to A mutation in CYP2D6 metabolism has not been reported. A polymerase
      chain reaction-based endonuclease digestion test was designed for the G/N1846
      polymorphism and 124 Chinese subjects were screened. With DNA sequencing, two
      other subjects showed the heterozygous G/A1846 and have a relatively high
      metabolic ratio of debrisoquine hydroxylation. The site-directed mutagenesis was 
      used to create recombinant CYP2D6 cDNA with T188, A1846, or C4268. The cDNA was
      then transfected into Rat-1 cells. The transfection was confirmed by Southern,
      Northern, and Western blots. Based on the same microsomal protein level, the
      bufuralol 1'-hydroxylation activity of CYP2D6(T188) or CYP2D6(A1846) was
      significantly lower than that of the wild-type CYP2D6. P34S mutation (C188 to T) 
      significantly decreased CYP2D6 activity. G169R mutation (G1846 to A) also
      decreased CYP2D6 activity and may further reduce the metabolic activity of CYP2D6
      protein with P34S, R296C, and S486T mutations.
FAU - Wang, S L
AU  - Wang SL
AD  - Department of Pharmacology, Medical College, National Cheng Kung University,
      Tainan, Taiwan.
FAU - Lai, M D
AU  - Lai MD
FAU - Huang, J D
AU  - Huang JD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (DNA, Complementary)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Alleles
MH  - Arginine/genetics
MH  - Cytochrome P-450 CYP2D6/*genetics/*metabolism
MH  - DNA, Complementary/genetics
MH  - Exons
MH  - Glycine/genetics
MH  - Humans
MH  - Mutagenesis, Site-Directed
MH  - *Mutation
EDAT- 1999/03/04 00:00
MHDA- 1999/03/04 00:01
CRDT- 1999/03/04 00:00
PHST- 1999/03/04 00:00 [pubmed]
PHST- 1999/03/04 00:01 [medline]
PHST- 1999/03/04 00:00 [entrez]
PST - ppublish
SO  - Drug Metab Dispos. 1999 Mar;27(3):385-8.