Growth hormone-regulated periportal expression of CYP2C7 in rat liver.
Most drug- and steroid-metabolizing cytochrome P450 (CYP) enzymes are expressed in the mammalian liver in a characteristic zonated pattern, with high expression in the downstream perivenous (centrilobular) region. Here, we report that CYP2C7, a member of the rat CYP2 family, is expressed preferentially in the opposite, periportal region. CYP2C7 mRNA, as detected by reverse transcription-polymerase chain reaction, was detected almost exclusively in cell lysates obtained from the periportal region, indicating a very steep acinar gradient. The amount of immunoreactive CYP2C7 protein in periportal cell lysates was also higher than in samples from the perivenous region. This gradient was reversed by hypophysectomy, which markedly and selectively reduced the periportal CYP2C7 protein content. Subsequent growth hormone infusion by osmotic minipumps restored the zonation by selectively increasing the amount of periportal CYP2C7 protein. Although hypophysectomy suppressed CYP2C7 mRNA and growth hormone counteracted it, regulation at this level did not appear to occur in a zone-specific fashion. This indicates that growth hormone-mediated zonal regulation of CYP2C7 protein has additional translational or posttranslational components. Ethanol treatment, which has been shown to affect growth hormone levels, significantly induced CYP2C7 mRNA, but not zone specifically. Our results demonstrate that growth hormone up-regulates the CYP2C7 gene by enhancing the expression of the protein specifically in the periportal liver region. Growth hormone may up-regulate other periportally expressed liver genes in a similar fashion.
Oinonen
T
T
Alcohol Research Center, National Public Health Institute, Helsinki, Finland.
Ronis
M
M
Wigell
T
T
Tohmo
K
K
Badger
T
T
Lindros
K O
KO
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015536:Down-Regulation; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000378:metabolism*; D007016:Hypophysectomy; D008099:Liver / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; C400322:cytochrome P-450 CYP2C subfamily; D000431:Ethanol; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System