Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice.
Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.
Morioka
Ichiro
I
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.
Wong
Ronald J
RJ
Abate
Aida
A
Vreman
Hendrik J
HJ
Contag
Christopher H
CH
Stevenson
David K
DK
D000284:Administration, Oral; D000818:Animals; D001663:Bilirubin / Q000096:biosynthesis; D003905:Deuteroporphyrins / Q000008:administration & dosage / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000188:drug therapy / Q000201:enzymology; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D011524:Protoporphyrins / Q000008:administration & dosage / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; C055421:tin mesoporphyrin; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D001663:Bilirubin