Selection of potential therapeutics based on in vivo spatiotemporal transcription patterns of heme oxygenase-1.
Heme oxygenase (HO), a key catabolic enzyme in the conversion of heme to bilirubin, is an ideal target for reducing bilirubin production and preventing pathological jaundice in newborn infants. Metalloporphyrins (Mps) have been well characterized as competitive inhibitors of HO and have been evaluated as potential chemopreventive agents for neonatal jaundice. However, in addition to reducing HO activity, many Mps have been shown to increase HO-1 transcription, which would likely reduce their potential therapeutic utility. The differential effects of Mps on the transcription of HO-1 were therefore evaluated in living transgenic (Tg) reporter mice. Of the compounds evaluated, we observed that zinc bis-glycol porphyrin (ZnBG), a potent inhibitor of HO enzyme activity, did not alter HO-1 transcription patterns in Tg mice. Whole body images of HO-1 transcription patterns did, however; reveal increases in HO-1 transcription in Tg mice after treatment with other Mps, heme and cadmium chloride (CdCl(2)). Intravenous injections of CdCl(2) resulted in expression patterns that differed in tempo and location from those observed in Tg mice treated with intraperitoneal injections. Spatiotemporal analyses of transcriptional regulation in living animals accelerated the assessment of an adverse effect of Mps by revealing different patterns of HO-1 transcription. Among the known inhibitors of HO enzyme activity that were evaluated in this study, ZnBG did not significantly affect HO-1 transcription and therefore may be well suited for the prevention of neonatal jaundice.
Zhang
Weisheng
W
Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University Medical Center, Stanford University, Stanford, CA 94305-5208, USA.
Contag
Pamela R
PR
Hardy
Jonathan
J
Zhao
Hui
H
Vreman
Hendrik J
HJ
Hajdena-Dawson
Monica
M
Wong
Ronald J
RJ
Stevenson
David K
DK
Contag
Christopher H
CH
D000818:Animals; D019256:Cadmium Chloride / Q000494:pharmacology; D003905:Deuteroporphyrins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D014158:Transcription, Genetic / Q000187:drug effects*
D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008665:Metalloporphyrins; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D006418:Heme; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019256:Cadmium Chloride