Haem arginate infusion stimulates haem oxygenase‐1 expression in healthy subjects

Abstract

BACKGROUND AND PURPOSEHaem oxygenase 1 (HO-1) is an inducible protein that plays a major protective role in conditions such as ischaemia-reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO-1 expression and its correlation with the GT length polymorphism (GTn) in the promoter of the HO-1 gene. EXPERIMENTAL APPROACHIn a dose-escalation, randomized, placebo-controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GTn genotype received intravenous HA. HO-1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period. KEY RESULTSWe found that the baseline mRNA levels of HO-1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose-dependent increase in the baseline corrected area under the curve values of HO-1 mRNA and protein over 48 h. The response of HO-1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups. CONCLUSIONS AND IMPLICATIONHA is an effective inducer of HO-1 in humans irrespective of the GTn genotype. The potential therapeutic application of HA needs to be evaluated in clinical trials. AbbreviationsAUC, area under the curve; BW, body weight; CO, carbon monoxide; GEE, generalised estimating equations; HA, haem arginate; HO, haem oxygenase; IRI, ischaemia-reperfusion injury; L/L, homozygous for the long GT repeat length polymorphism in the promoter of the HO-1 gene; PBMCs, perhipheral blood mononuclear cells; S/S, homozygous for the short GT repeat length polymorphism in the promoter of the HO-1 gene.

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms

“…This "dependence" has been plausibly linked to the induction of hepatic haem oxygenase-1 expression reported in healthy subjects (Doberer et al 2010). Other studies have provided evidence of significant toxicity associated with intravenous haem, with induction of endothelial activation and a procoagulant state, and it is uncertain whether regular administration over many years is actually beneficial.…”

Heme as a Target for Therapeutic Interventions

“…A compound with better potential for translation into the clinic might be heme arginate, which appears to be less toxic than heme (Jeney et al, 2002) and is an approved therapy for treatment of hepatic porphyrias in various European countries (Mustajoki et al, 1986; Kordac et al, 1989). Notably, heme arginate was found to up-regulate HO-1 not only in healthy individuals (Doberer et al, 2010), but also in patients receiving deceased donor renal transplants in a recent phase IIB trial (Thomas et al, 2016). Nevertheless, further studies are required to establish the feasibility of heme arginate for clinical applications.…”

Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria

“…The standard cut-off scores of BDI-II are: minimal depression (0-9), mild depression (10)(11)(12)(13)(14)(15)(16)(17)(18); moderate depression (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and severe depression . The standard cutoff scores of BAI are low anxiety (0-21), moderate anxiety (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and severe anxiety (36-63).…”

“…Thromboembolic disease and iron overload (a dose of 250 mg of heme arginate contains 22.7 mg of iron) are also side effects associated with repeated courses of this therapy (18). Even though prophylactic heme appears to be beneficial in patients with recurrent attacks, life-long exposure to drugs for the control of symptoms may cause considerable adverse events that greatly impair quality of life (16,17). Thus alternative therapies for severe AIP are needed.…”

“…Although heme represses ALAS, thus blocking heme biosynthesis, it also activates hemeoxygenase-1 (EC:1.14.99.3), which in turn promotes acute attack recurrences and the decline of the therapeutic efficacy (16,17). Thromboembolic disease and iron overload (a dose of 250 mg of heme arginate contains 22.7 mg of iron) are also side effects associated with repeated courses of this therapy (18).…”