Carbon Monoxide as a Potential Therapeutic Agent: A Molecular Analysis of Its Safety Profiles

Abstract

Carbon monoxide (CO) is endogenously produced in mammals, with blood concentrations in the high micromolar range in the hemoglobin-bound form. Further, CO has shown therapeutic effects in various animal models. Despite its reputation as a poisonous gas at high concentrations, we show that CO should have a wide enough safety margin for therapeutic applications. The analysis considers a large number of factors including levels of endogenous CO, its safety margin in comparison to commonly encountered biomolecules or drugs, anticipated enhanced safety profiles when delivered via a noninhalation mode, and the large amount of safety data from human clinical trials. It should be emphasized that having a wide enough safety margin for therapeutic use does not mean that it is benign or safe to the general public, even at low doses. We defer the latter to public health experts. Importantly, this Perspective is written for drug discovery professionals and not the general public.

Figure 1

Endogenous production of CO. The major endogenous source of CO is heme degradation by heme oxygenase. Figure adapted from images created with BioRender.com.

Figure 2

CO released into the ophthalmic venous blood (OphVB) depending on the intensity of sunlight. (A) Light triggered increase in endogenous CO. (B) The change in CO levels (mmol/mL) in venous blood of 11 individual pigs after 80 min of 5000 lx white light exposure. Adapted from ref (84). Copyright 2017 Elsevier. Figure adapted from images created with BioRender.com.

Figure 3

Human clinical trials of inhaled CO gas. CO inhalation conditions are the following: (a) 200 ppm of CO for 90 min/day for 5 days; (b) 1000 ppm of CO for 30 min at the rate of twice every minute, with a 1 min break every 5 min; (c) 125 ppm of CO for 2 h/day for 4 days; and (d) 100–200 ppm of CO for 2 h/day twice a week for 12 weeks. Figure adapted from images created with BioRender.com.

Figure 4

Comparison of CO concentrations under various conditions with commonly known endogenous biomolecules and commonly used drugs. The concentration of CO was converted from COHb%: endogenous COHb level, 1–2% (corresponding to 75–150 μM); cigarette smokers’ COHb level, 4.2–39% (corresponding to 0.3–2.0 mM); COHb safety threshold level in an FDA-approved clinical trial of kidney transplantation, 14% (corresponding to 1.05 mM); and COHb level for imminent threat of death by CO poisoning, 65% (corresponding to 4.9 mM). The concentrations of inorganic irons, biomolecules, and drugs are shown in Tables 1–3 with references. The toxic levels of inorganic irons, biomolecules, and drugs are based on case studies shown in Tables 1–3 with references. Figure adapted from images created with BioRender.com.

Figure 5

Mechanisms of the CO toxicity. ^aThree of the 10 dogs died on days 15–42 from unrelated causes. Figure adapted from images created with BioRender.com.

Figure 6

Differences in Hb functions between CO gas inhalation and COHb transfusion. (A) CO gas inhalation leading to a COHb level of 50%: (i) Calculated distribution of all forms of Hb in the blood when CO gas binds to Hb.^, (ii) COHb shifts the oxygen–hemoglobin dissociation curve to the left and transforms it into a hyperbolic shape. The percent saturation of Hb with oxygen (SaO₂%) is plotted against the partial pressure of oxygen (PO₂). (B) Transfusion of CO-saturated Hb (i) leads to two distinct forms of Hb in the blood and (ii) allows the oxygen-hemoglobin dissociation curve to remain the same as the normal curve when SaO₂% is plotted against PO₂. Figure adapted from images created with BioRender.com.

Figure 7

Binding equilibria between hemoglobin and (A) CO and (B) O₂.

Figure 8

Mitochondrial-targeted CO delivery. (A) An enrichment-triggered release approach to target CO to the mitochondrion. Fluorescence images show colocalization of the product following a Diels–Alder click reaction with mitochondrial tracker MitoTracker Deep Red in RAW264.7 cells. Adapted from ref (53). Copyright 2018 Springer Nature. (B) Mitochondria-targeted PhotoCORM approach for mitochondrial bioenergetics studies. Confocal microscopy image showing colocalization of mitochondrion-targeted PhotoCORM with MitoTracker Red CMXRos in A549 cells. Adapted from ref (295). Copyright 2018 American Chemical Society. Figure adapted from images created with BioRender.com.