Correlation of Cytochrome P450 Oxidoreductase Expression with the Expression of 10 Isoforms of Cytochrome P450 in Human Liver.
Human cytochrome P450 oxidoreductase (POR) provides electrons for all microsomal cytochromes P450 (P450s) and plays an indispensable role in drug metabolism catalyzed by this family of enzymes. We evaluated 100 human liver samples and found that POR protein content varied 12.8-fold, from 12.59 to 160.97 pmol/mg, with a median value of 67.99 pmol/mg; POR mRNA expression varied by 26.4-fold. POR activity was less variable with a median value of 56.05 nmol/min per milligram. Cigarette smoking and alcohol consumption clearly influenced POR activity. Liver samples with a 2286822 TT genotype had significantly higher POR mRNA expression than samples with CT genotype. Homozygous carriers of POR2286822C>T, 2286823G>A, and 3823884A>C had significantly lower POR protein levels compared with the corresponding heterozygous carriers. Liver samples from individuals homozygous at 286823G>A, 1135612A>G, and 10954732G>A generally had lower POR activity levels than those from heterozygous or wild-type samples, whereas the common variant POR*28 significantly increased POR activity. There was a strong association between POR and the expression of P450 isoforms at the mRNA and protein level, whereas the relationship at the activity level, as well as the effect of POR protein content on P450 activity, was less pronounced. POR transcription was strongly correlated with both hepatocyte nuclear factor 4 alpha and pregnane X receptor mRNA levels. In conclusion, we have elucidated some potentially important correlations between POR single-nucleotide polymorphisms and POR expression in the Chinese population and have developed a database that correlates POR expression with the expression and activity of 10 P450s important in drug metabolism.
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Hai-Feng
HF
Zhang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Zhi-Hui
ZH
Li
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Jia-Yu
JY
Liu
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Ting-Ting
TT
Liu
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Ping
P
Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Yan
Y
Fang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Jun
J
Zhou
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Ming-Zhu
MZ
Cui
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Na
N
Gao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Xin
X
Tian
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Jie
J
Gao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Qiang
Q
Wen
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.
Lin-Jing
LJ
Jia
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China qiaohl@zzu.edu.cn.
Hai-Ling
HL
Qiao
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism; D002681:China; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D016208:Databases, Factual; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000235:genetics / Q000378:metabolism
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007527:Isoenzymes; C000602470:POR protein, human; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System