Induction of cytochrome CYP4F3A in all-trans-retinoic acid-treated HL60 cells.
Cytochrome P-450 CYP4F3A catalyzes the inactivation of leukotriene B(4) by omega-hydroxylation, an activity of which is specifically expressed in human neutrophils. Here, we examined expression of the LTB(4) omega-hydroxylating activity during the differentiation of HL60 cells, an acute promyelocytic leukemia cell line, in the presence of various inducers. Among the inducers used, all-trans-retinoic acid (ATRA) most strongly induces the LTB(4) omega-hydroxylating activity in a dose-dependent manner. The time course of the induction of the omega-hydroxylating activity correlates well with that of the superoxide-generating activity, indicative of cell differentiation. ATRA-treated cell microsomes convert LTB(4) to its 20-hydroxyl derivative under aerobic conditions in the present of NADPH. The reaction is inhibited by carbon monoxide, an inhibitor of cytochrome P-450, and by antibodies raised against NADPH-P-450 reductase. CYP4F3A appears to be responsible for the LTB(4) omega-hydroxylase activity, based on the following observations: expression of the mRNA for CYP4F3A is observed together with the induction of LTB(4) omega-hydroxylating activity in ATRA-treated HL60 cells; and the apparent K(m) values for the omega-hydroxylation of LTB(4) and lipoxin B(4) by ATRA-treated cell microsomes are essentially the same as those of CYP4F3A in human neutrophil microsomes.
Mizukami
Yoichi
Y
Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. mizukami@yamaguchi-u.ac.jp
Sumimoto
Hideki
H
Takeshige
Koichiro
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D003580:Cytochromes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000145:classification / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003580:Cytochromes; D007527:Isoenzymes; D013481:Superoxides; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human; C040780:leukotriene B4 20-hydroxylase