Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism.
Biol Pharm Bull
; 24(12): 1427-30, 2001 Dec.
Article
in En
| MEDLINE
| ID: mdl-11767116
ABSTRACT
By sequencing genomic DNA from 73 established cell lines derived from Japanese individuals, we detected 9 single nucleotide polymorphisms (SNPs) in the CYP2C8 gene. Of them, 3 exonic SNPs resulted in amino acid alterations (g416a, R139K; a1196g, K399R; c1210g, P404A). The first two alterations were detected concurrently in one cell line and thought to be the same as CYP2C8*3. To examine the effects of these amino acid alterations on CYP2C8 function, wild-type and four types of variant CYP2C8 cDNA constructs (R139K, K399R, R139K/K399R and P404A) were transfected into Hep G2 cells and their paclitaxel 6a-hydroxylase activities were determined in vitro. Km values were not significantly different from that of the wild-type in any of the variants studied. The variant R139K/K399R showed reduced values for Vmax and clearance (Vmax/Km) similar to those of its single variant, R139K. The variant P404A also showed a significantly lowered clearance due to reduced level of protein expression. These results suggest that not only the double variant (R139K/K399R, CYP2C8*3) but also our novel variant P404A in the CYP2C8 gene are less efficient in paclitaxel metabolism.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Steroid Hydroxylases
/
Aryl Hydrocarbon Hydroxylases
/
Paclitaxel
/
Polymorphism, Single Nucleotide
/
Cytochrome P-450 Enzyme System
/
Steroid 16-alpha-Hydroxylase
Limits:
Humans
Language:
En
Journal:
Biol Pharm Bull
Year:
2001
Document type:
Article