Heme oxygenase (HO) catalyzes the degradation of heme to produce bilirubin. Because excess bilirubin production can lead to the development of jaundice, use of HO-inhibiting drugs, such as metalloporphyrin analogs of heme, may be a promising treatment strategy for the prevention of neonatal hyperbilirubinemia. We and our collaborators reported that imidazole dioxolanes also can inhibit in vitro HO activity with selectivity for the inducible HO-1 isozyme and do not affect NOS or sGC, in contrast to metalloporphyrins. The objective of this study was to investigate the efficacy of the imidazole dioxolane Azalanstat (AZA) toward inhibiting in vivo HO enzyme activity in newborn mice. AZA (500 μmol/kg) or vehicle (7.9% cyclodextran) was administered to 7-day-old FVB mice via intraperitoneal injections. At 0.25, 0.5, 2, 3, and 24 hours after administration, mice were sacrificed and liver, spleen, and brain harvested. Tissues were then sonicated in buffer. HO activity was quantitated by gas chromatography and calculated as pmoles of carbon monoxide (CO) produced/h/mg fresh weight. Percent inhibition (mean ± SD) of tissue HO activity from treated versus control mice at each time point is shown below (n ≥ 3 for each tissue, *p ≤ .05):
HO activity was maximally inhibited (in bold) in the spleen (54%) and brain (40%) within 30 minutes and in the liver (27%) within 3 hours after AZA treatment. HO activity in the spleen and liver returned to control levels within 24 hours in contrast to the brain, where significant inhibition remained. At 0.25 to 3 hours after AZA treatment, the spleen was most effectively inhibited, followed by the brain and then the liver. We conclude that AZA effectively inhibits HO activity, and its action is immediate and short acting as well as tissue dependent. Thus, imidazole dioxolanes may be attractive alternative compounds for use in the treatment of neonatal jaundice. Further study is required to identify more potent derivatives and to elucidate their particular mechanism of inhibition.
This work was study was supported in part by National Institutes of Health grant #HL68703, the Mary L. Johnson Research Fund, and the Christopher Hess Research Fund.
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