Genetic polymorphism of cytochrome P450 4F2, vitamin E level and histological response in adults and children with nonalcoholic fatty liver disease who participated in PIVENS and TONIC clinical trials.
Vitamin E improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but with significant inter-individual variability in its efficacy. Cytochrome P450 4F2 (CYP4F2) is the major enzyme metabolizing Vit E, with two common genetic variants (V433M, rs2108622 and W12G, rs3093105) found to alter its activity. We investigated the relationship between CYP4F2 genotypes, α-tocopherol levels and histological improvement in these two trials. V433M and W12G variants were genotyped in TONIC (n = 155) and PIVENS (n = 213) DNA samples. The relationships between CYP4F2 genotypes, plasma α-tocopherol levels at baseline and weeks 48 (w48) and 96 (w96) and histological end points (overall improvement in liver histology and resolution of NASH) were investigated. As a result, the V433M genotype was significantly associated with baseline plasma α-tocopherol in the TONIC trial (p = 0.004), but not in PIVENS. Among those receiving Vit E treatment, CYP4F2 V433M genotype was associated with significantly decreased plasma α-tocopherol levels at w48 (p = 0.003 for PIVENS and p = 0.026 for TONIC) but not at w96. The w96 α-tocopherol level was significantly associated with resolution of NASH (p = 0.006) and overall histology improvement (p = 0.021)in the PIVENS, but not in the TONIC trial. There was no significant association between CYP4F2 genotypes and histological end points in either trial. Our study suggested the a moderate role of CYP4F2 polymorphisms in affecting the pharmacokinetics of Vit E as a therapeutic agent. In addition, there may be age-dependent relationship between CYP4F2 genetic variability and Vit E pharmacokinetics in NAFLD.
Department of Medicinal Chemistry and Molecular Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Shaminie
S
Athinarayanan
Department of Medicinal Chemistry and Molecular Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Rongrong
R
Wei
Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
Min
M
Zhang
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Shaochun
S
Bai
Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
Maret G
MG
Traber
Johns Hopkins Bloomberg School of Public Health, Baltimore, Massachusetts, United States of America.
Katherine
K
Yates
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Oscar W
OW
Cummings
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Jean
J
Molleston
Department of Medicinal Chemistry and Molecular Medicine, Purdue University, West Lafayette, Indiana, United States of America; Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Wanqing
W
Liu
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Naga
N
Chalasani
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014810:Vitamin E / Q000097:blood* / Q000627:therapeutic use*; D024502:alpha-Tocopherol / Q000097:blood
D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; D024502:alpha-Tocopherol