Cytochrome 3A and 2E1 in human liver tissue: Individual variations among normal Japanese subjects.
OBJECTIVE
The metabolism of drugs, xenobiotic compounds, and other endogenous/exogenous substrates generally begins with their oxidation through cytochrome P450 (CYP). The results of recent pharmacogenetic analyses have demonstrated CYP's polymorphisms to be related to individual differences in metabolism, but only a limited number of CYP3A4 and CYP2E1 variant alleles influence enzymatic activities. Therefore, CYP gene expression profiling of both normal and pathological human livers should provide critical information for an evaluation of the biological significance of CYPs.


METHODS
In our present study, we first characterized the individual differences in CYP3A4 and CYP2E1 expression levels among Japanese normal or non-pathological liver tissue obtained from autopsy or surgery using immunohistochemistry and quantitative RT-PCR array of phase I metabolic enzymes with combined laser capture microscopy and qPCR analysis.


RESULTS
Both CYP3A4 and CYP2E1 mRNA and proteins were predominantly detected in hepatocytes surrounding central veins in normal liver, but there were marked individual differences in both CYP3A4 and CYP2E1 mRNA and proteins among the 23 Japanese subjects examined. Individual differences in CYP3A and CYP2E1 subtypes were also detected in the livers obtained from monozygotic neonatal Japanese female twins with different survival periods. CYP3A and CYP2E1-positive cells were decreased in number in non-pathological hepatocytes of diseased livers compared to those in disease-free livers from autopsy.


CONCLUSIONS
The above results suggest that individual differences in CYP3A4 and CYP2E1 exist among normal human liver tissues and in non-pathological hepatocytes between diseased and normal liver, and these differences may be important in evaluating the pharmacodynamics of various substances.
Hata
Shuko
S
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Miki
Yasuhiro
Y
Fujishima
Fumiyoshi
F
Sato
Ryuichiro
R
Okaue
Adoru
A
Abe
Keiko
K
Ishida
Kazuyuki
K
Akahira
Jun-ichi
J
Unno
Michiaki
M
Sasano
Hironobu
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D002648:Child; D002675:Child, Preschool; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D005234:Fatty Liver / Q000201:enzymology; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008099:Liver / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014430:Twins, Monozygotic; D015262:Xenobiotics / Q000378:metabolism; D055815:Young Adult
D012333:RNA, Messenger; D015262:Xenobiotics; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A