Systemic Effects of Orally-Administered Zinc and Tin (IV) Metalloporphyrins on Heme Oxygenase Expression in Mice

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Abstract
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 μmol/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 3h of SnMP treatment and persisted beyond 48h. Bilirubin production decreased 15% and 9% by 3h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3h with inhibitory effects decreasing in the order: SnMP ≥ ZnBG ≥ ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24h. 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.