Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation.

Article Details

Citation

Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M

Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation.

Mol Pharmacol. 1994 Sep;46(3):452-9.

PubMed ID
7935325 [ View in PubMed
]
Abstract

Cytochrome P4502D6 (CYP2D6) catalyzes the oxidative metabolism of several clinically important classes of drugs. Many of these have lower metabolic clearance rates among Chinese, compared with Caucasians, and are prescribed at lower doses for Asian patients. We have now evaluated the molecular genetic basis for this interethnic difference in drug metabolism. The CYP2D loci from two Chinese subjects, one homozygous for the XbaI 44-kilobase haplotype and one homozygous for the XbaI 29-kilobase haplotype, were cloned and characterized. Sequence analysis revealed two variant CYP2D6 genes, CYP2D6Ch1 and CYP2D6Ch2, having mutations yielding two and eight amino acid substitutions, respectively. Exon 9 of the CYP2D6Ch2 gene contained a sequence of 49 bases originating from the pseudogene CYP2D7P. In addition, mutations in the 5' flanking region common to both CYP2D6Ch genes were found. To evaluate the origin of the detrimental mutation in the genes, parts of the 5' flanking regions were introduced into a Hep G2/simian virus 40 expression system with chloramphenicol acetyltransferase as a reporter gene, and transfected cells were analyzed for activity. The ability of the upstream regions to bind nuclear factors was also evaluated using gel-shift analysis. Furthermore, several chimeric constructs of the CYP2D6wt and CYP2D6Ch genes were made, inserted into pCMV2 vectors, and expressed in COS-1 cells. A part of the upstream region of base pairs -1407 to -1068 was found to constitute an enhancer element, but the CYP2D6Ch-specific mutations did not influence the chloramphenicol acetyltransferase activity in the expression system. In contrast, expression of the chimeric genes revealed that the detrimental mutation of the CYP2D6Ch genes was C188-->T, causing a Pro34-->Ser amino acid substitution in a region that is a highly conserved in cytochromes P450 belonging to gene families 1 and 2. This substitution caused expression of a more unstable gene product, as evident from comparison of the relative levels of CYP2D6 mRNA, CYP2D6 protein, and bufuralol 1'-hydroxylase activities in pCMV2-CYP2D6-transfected COS-1 cells. Allele-specific polymerase chain reaction analysis of genomic DNA from 90 Chinese individuals revealed that the CYP2D6Ch1 allele was the most common one and its distribution correlated well with a higher metabolic ratio for debrisoquine. These data demonstrate that important interethnic differences exist in the structure of the CYP2D locus, and they suggest that the frequent distribution of the C188-->T mutation among the CYP2D6Ch genes explains the lower capacity among Chinese to metabolize drugs that are substrates of CYP2D6, such as antidepressants and neuroleptic agents.

DrugBank Data that Cites this Article

Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
MetoprololCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
ADR InferredIncreased risk of slow heart rate (bradycardia)Details
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, nausea, vomiting and diarrheaDetails
CodeineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
AmitriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ImipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
DextromethorphanCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
NortriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
TamoxifenCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor response to drug treatment, shorter time to relapseDetails
DesipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ClomipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
AtomoxetineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*36Not Available
  • 100C>T (rs1065852)
  • -1426C>T
  • variable number of A’s in the region -1258 to -1237a
show all 9 …
Effect InferredPoor drug metabolizer, increased side effects.Details