The Production of Carbon Monoxide from Hemoglobin In Vivo*

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Abstract
Dogs anesthetized with pentobarbital were shown to produce carbon monoxide at an average rate of 0.21 ± (SD) 0.05 ml per hour. After intravenous injection of erythrocytes damaged by incubation with N-ethylmaleimide, CO was produced in excess of base-line production for 3 to 4 hours with an average yield of 0.89 ± (SE) 0.046 μmole of carbon monoxide to 1 μmole of heme degraded. After intravenous injection of N-ethylmaleimide (NEM)-treated erythrocytes containing hemoglobin labeled with 14carbon, 14CO was produced. Its specific activity was approximately one-eighth that of the injected heme. It was also produced after intravenous injection of solutions of hemoglobin-14C and of reconstituted methemoglobin containing hemin-14C, but not after injections of methemoglobin containing globin-14C. The average yields of 14CO from metabolized heme in the experiments with damaged erythrocytes and hemoglobin solutions were 89 ± (SE) 4.6 and 97 ± (SE) 17.0%, respectively. These results demonstrate that the CO produced during hemoglobin degradation arises from the heme moiety. The yield of 14CO after injection of hemoglobin-14C solutions decreased significantly to values of 35 and 42% in two experiments when exogenous CO was added to the body stores, resulting in blood carboxyhemoglobin levels of 11.3 and 13.2% saturation. This finding suggests that oxidative metabolism is required during catabolism of hemoglobin to CO and that carboxy-hemoglobin levels in this range are sufficient to cause inhibition. After intravenous injection of either hemin-14C or protoporphyrin-14C, 14CO was also produced. After injection of protoporphyrin-14C labeled bilirubin was isolated from gall bladder bile, and labeled hemin was isolated from the liver. It is thus very likely that protoporphyrin is converted to heme before the formation of CO. There was a large difference between the maximal rates of catabolism of hemoglobin to CO observed after injection of damaged erythrocytes and hemoglobin solutions. The limiting parameters in these processes are not yet clear.