A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin.
A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.
Ishikawa
Chikako
C
Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Ozaki
Hiroshi
H
Internal Medicine, Sakura Hospital, School of Medicine, Toho University, Chiba, Japan.
Nakajima
Toshiaki
T
Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ishii
Toshihiro
T
Department of Pharmacy, Faculty of Medicine, Sakura Hospital, Toho University, Chiba, Japan.
Kanai
Saburo
S
Department of Pharmacy, Faculty of Medicine, Sakura Hospital, Toho University, Chiba, Japan.
Anjo
Saeko
S
Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Shirai
Kohji
K
Internal Medicine, Sakura Hospital, School of Medicine, Toho University, Chiba, Japan.
Inoue
Ituro
I
Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. ituro@ims.u-tokyo.ac.jp.
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000235:genetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C086276:cerivastatin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8