Induction of rabbit lung CYP4A4 prostaglandin omega-hydroxylase by various steroid hormones.
Cytochrome P4504A4 (CYP4A4) is expressed at low basal levels in adult rabbit lungs, but is significantly induced during pregnancy by an unknown mechanism. As the gradual rise in CYP4A4 levels appears to coincide with the progressive increase in several steroid hormones throughout pregnancy, we examined the induction of CYP4A4 after treatment with various steroid hormones by monitoring both the CYP4A4 mRNA level and the CYP4A4-specific prostaglandin E(1) (PGE(1)) omega-hydroxylation reaction in rabbit lung microsomes. Treatment with progesterone and/or a synthetic glucocorticoid (dexamethasone) resulted in a significant increase in PGE(1) omega-hydroxylase activity, whereas estradiol, aldosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate did not. These studies indicated that dexamethasone was a more potent inducer of CYP4A4 than progesterone. Simultaneous injection of dexamethasone and glucocorticoid/progesterone antagonists (RU38486, RU40555, or RU43044) inhibited the increase in PGE(1) omega-hydroxylase activity as well as mRNA levels by approximately 50%. In addition, simultaneous treatment with both dexamethasone and progesterone did not result in an additive or synergistic effect on PGE(1) omega-hydroxylase activity. These data indicate that, while distinctive receptors for glucocorticoid and/or progesterone are involved, induction may also require common or interacting regulatory elements (yet to be determined) in the CYP4A4 gene. These findings implicate both of these steroid receptors (PR/GR) in the induction of CYP4A4 in rabbit lung.
McCabe
T J
TJ
Department of Pharmacology, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
Roman
L J
LJ
Masters
B S
BS
D000527:Alprostadil / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013256:Steroids / Q000494:pharmacology*
D006727:Hormone Antagonists; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013256:Steroids; D011374:Progesterone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C026961:prostaglandin omega hydroxylases; D000527:Alprostadil