Inhibition of heme oxygenase activity in newborn mice by azalanstat.
Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, may be an ideal strategy for preventing neonatal jaundice. Although natural and synthetic heme analogs, called metalloporphyrins (Mps), have been extensively investigated for this purpose, some Mps are phototoxic, affect the activity of other enzymes, or induce HO-1 transcription-properties that may limit their clinical use. Another class of compounds, imidazole-dioxolanes, has been shown to selectively inhibit the inducible isozyme HO-1. Therefore, we investigated the efficacy of azalanstat (AZA), an imidazole-dioxolane, towards inhibiting HO activity in 7-day-old mice. We found that a single dose of AZA at 500 micromol.kg(-1) body mass (BM) administered i.p. significantly inhibited HO activity and reduced in vivo bilirubin production. In the spleen, HO inhibition (>50%) was observed within 0.25-3 h after administration. After 24 h, however, spleen HO activity, HO-1 protein, and HO-1 mRNA levels significantly increased 1.2-, 2.4-, and 4.0-fold, respectively. We conclude that AZA effectively inhibits in vivo HO activity only at a high dose and that it also induces spleen HO-1 gene transcription. Therefore, other imidazole-dioxolanes should be evaluated to determine whether they are more potent than AZA for use in treating neonatal jaundice.
Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Takeshi
T
Morisawa
Ronald J
RJ
Wong
Vinod K
VK
Bhutani
Hendrik J
HJ
Vreman
David K
DK
Stevenson
D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D049449:Luminescence; D008705:Methemalbumin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009249:NADP / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013440:Sulfides / Q000627:therapeutic use*; D014018:Tissue Distribution; D014158:Transcription, Genetic / Q000187:drug effects
D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D008705:Methemalbumin; D012333:RNA, Messenger; D013440:Sulfides; C082410:azalanstat; D009249:NADP; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin