OBJECTIVE: Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease. STUDY DESIGN: We determined for the deutero-, proto-, meso- and bis-glycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I(50)) of HO-1 and HO-2 activities in rat spleen and brain tissue. RESULT: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. CONCLUSION: Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.
OBJECTIVE:Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease. STUDY DESIGN: We determined for the deutero-, proto-,meso- and bis-glycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I(50)) of HO-1 and HO-2 activities in rat spleen and brain tissue. RESULT: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. CONCLUSION:Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.
Authors: Tiffany G Baker; Soumen Roy; Carlene S Brandon; Inga K Kramarenko; Shimon P Francis; Mona Taleb; Keely M Marshall; Reto Schwendener; Fu-Shing Lee; Lisa L Cunningham Journal: J Assoc Res Otolaryngol Date: 2014-09-27
Authors: Susan E Wiedmeier; Timothy M Bahr; Robin K Ohls; Thomas R Christensen; Vickie L Baer; Sarah J Ilstrup; Kelly Cail; Robert D Christensen Journal: J Perinatol Date: 2020-07-15 Impact factor: 2.521
Authors: Mona N Rahman; Dragic Vukomanovic; Jason Z Vlahakis; Walter A Szarek; Kanji Nakatsu; Zongchao Jia Journal: J R Soc Interface Date: 2012-11-08 Impact factor: 4.118
Authors: James W Opzoomer; Jonathan Caron; Tamara Muliaditan; Mary Okesola; Paris Kosti; Sharanpreet Lall; Mieke Van Hemelrijck; Francesco Dazzi; Andrew Tutt; Anita Grigoriadis; Cheryl E Gillett; Stephen F Madden; Joy M Burchell; Shahram Kordasti; Sandra S Diebold; James F Spicer; James N Arnold Journal: Clin Cancer Res Date: 2018-01-16 Impact factor: 12.531