Expression of CYP27A, a gene encoding a vitamin D-25 hydroxylase in human liver and kidney.
Vitamin D3 (D3) is not active but must be hydroxylated at C-25 in liver before acquiring its hormonal potential in the kidney. The sterol-27 hydroxylase (gene symbol: CYP27A) catalyses the oxidation of sterol side chain in bile acid synthesis but the enzyme is also known as a D3-25 hydroxylase. The study examined the expression of the gene encoding CYP27A in adult and fetal human livers and kidneys. Thirty-nine adults (18 men and 21 women; mean age 58 years in men and 57 years in women) and three normal fetuses gestational age 17-19 weeks were studied. Tissue CYP27A mRNA and serum 25OHD concentrations were measured. Normal specimens: CYP27A transcript was found to be higher in adult than in fetal livers but its expression was similar in adult and fetal kidneys. In fetuses, no difference was observed between CYP27A levels in livers and kidneys. In adult livers CYP27A levels were higher in women than in men. Hepatic CYP27A mRNA and serum 25OHD concentrations were both found to be higher in summer than in winter. Multiple linear regression analyses indicate that the season of the year and the serum 25OHD concentrations (but not 1,25(OH)2D concentrations) are the best predictors of CYP27A mRNA abundance in normal adult livers. In situ hybridization illustrates a clear label in hepatocytes which increases in intensity in the perivenous region of the hepatic acinus. Pathological specimens: In one man with an hepatic carcinoma there was a very large increase in CYP27A (> 1000 fold) compared to the level found in the normal liver. In that patient, serum 25OHD concentrations were found to be high considering the level of CYP27A mRNA in the normal hepatic area suggesting that the neoplastic tissue contributed to the C-25 hydroxylation of vitamin D. Specimens obtained from two patients suffering from focal hepatic hyperplasia indicate that in one case the level of CYP27A mRNA was twice as high in the pathological than in the normal area while in the other its levels were similar in both areas. No difference in the CYP27A transcript was observed between specimens obtained from normal areas and those obtained form either an hepatic adenoma or from two intrahepatic colonic metastases. CYP27A is present not only in the human adult liver but also in the adult kidney, and in the fetal liver and kidney. Our findings illustrate that CYP27A can be significantly upregulated in certain pathological situations such as in hepatic carcinoma and that the neoplastic tissue could contribute to the circulating concentration of 25OHD.
Gascon-Barré
M
M
Département de Pharmacologie, Faculté de médecine Université de Montréal, Québec, Canada. marielle.gascon.barre@umontreal.ca
Demers
C
C
Ghrab
O
O
Theodoropoulos
C
C
Lapointe
R
R
Jones
G
G
Valiquette
L
L
Ménard
D
D
D000236:Adenoma / Q000378:metabolism; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D003110:Colonic Neoplasms / Q000378:metabolism / Q000556:secondary; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D016014:Linear Models; D008099:Liver / Q000196:embryology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis*; D012621:Seasons; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000378:metabolism
D012333:RNA, Messenger; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase