Changes in the expression of cytochrome P450 genes in hemin-induced differentiated K562 cells.
We have previously reported the expression of CYP genes in human myeloblastic and lymphoid cell lines, and the induction of the CYP3A4 and GSTP1 genes by oxidative stress in the human erythroleukemia cell line, K562. To further elucidate the role of drug metabolizing enzymes in hematogenesis, we have characterized the expression of CYP genes in hemin-induced differentiated K562 cells. After incubation with 50 microM hemin for 3 d, the expression of CYP1A1 and CYP3A4 genes was induced by 2.5- and 3.5-fold, respectively. In contrast, the CYP1B1 and CYP2E1 genes were downregulated in these cells to below 10% of the control levels. Moreover, these changes correlated with the hemin dose and culture time. Metabolism of midazolam, a probe substrate for CYP3A4, in the differentiated K562 cells increased by 2-folds, suggesting that the induction of CYP3A4 activity is consistent with the mRNA level. If these changes in the CYP expression profile in hematopoietic cells occurred, the susceptibility to xenobiotics and/or the therapeutic drugs of the cells might be influenced, and it also affects the metabolism of endogenous substrates, such as steroids and prostaglandins.
Nagai
Fusako
F
Kyoritsu University of Pharmacy, Tokyo, Japan.
Shimizu
Mikiko
M
Sakamoto
Tomoko
T
Kobayashi
Takeshi
T
Tamura
Hiroomi
H
D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis; D020014:K562 Cells; D008874:Midazolam / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D012333:RNA, Messenger; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam