Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Hemoglobin adduction and impaired oxygen transport define the etiology of pyrrolizidine alkaloid-induced pulmonary arterial hypertension.
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Zhang Caibin, Huang Tianyang, Guo Xiaokai, Fan Yujian, Song Zijing, Ma Jiang, He Yisheng
Аннотация
BACKGROUND: Pyrrolizidine alkaloids (PAs), particularly monocrotaline (MCT), are common phytotoxins known to induce pulmonary arterial hypertension (PAH), a progressive and fatal cardiopulmonary disease. However, the specific mechanism initiating PAH and the basis for the differing toxic potencies among PAs, such as MCT and retrorsine (RTS), remain undefined.
PURPOSE: This study aimed to investigate the mechanistic basis for the marked difference in pulmonary toxicity between two representative PAs, MCT and RTS. We specifically tested the hypothesis that the severity of PA-induced lung injury is determined by the extent of hemoglobin adduction within red blood cells (RBCs) and the consequent impairment of oxygen transport.
STUDY DESIGN: We employed a comparative toxicological design using rat models, treating them with equimolar doses of MCT and RTS, to assess and compare their respective toxicological pathways and resulting pulmonary injury.
METHODS: Rats were administered MCT or RTS. Dehydropyrrolizidine alkaloid (DHPA) adduct formation on RBC hemoglobin was profiled using proteomics. Pulmonary hemodynamics, pulmonary vascular remodeling, and systemic hypoxia levels were subsequently measured.
RESULTS: DHPAs selectively and covalently bound to specific residues (D74, E91, H93, K133) on the hemoglobin β-1 chain, critically impairing the oxygen-carrying capacity of RBCs. MCT exposure resulted in significantly higher levels of pyrrole-hemoglobin adducts (approximately 95% binding) compared to RTS (approximately 70% binding). This higher adduction rate led to more severe systemic hypoxia, which was consistently associated with greater pulmonary arterial endothelial activation and more severe PAH in the MCT group.
CONCLUSION: The severity of PA-induced PAH is directly correlated with the degree of hemoglobin adduction and resulting hypoxia. Hemoglobin adduction and impaired oxygen transport are critical, upstream events that define the etiology of PA-induced pulmonary arterial hypertension.
PURPOSE: This study aimed to investigate the mechanistic basis for the marked difference in pulmonary toxicity between two representative PAs, MCT and RTS. We specifically tested the hypothesis that the severity of PA-induced lung injury is determined by the extent of hemoglobin adduction within red blood cells (RBCs) and the consequent impairment of oxygen transport.
STUDY DESIGN: We employed a comparative toxicological design using rat models, treating them with equimolar doses of MCT and RTS, to assess and compare their respective toxicological pathways and resulting pulmonary injury.
METHODS: Rats were administered MCT or RTS. Dehydropyrrolizidine alkaloid (DHPA) adduct formation on RBC hemoglobin was profiled using proteomics. Pulmonary hemodynamics, pulmonary vascular remodeling, and systemic hypoxia levels were subsequently measured.
RESULTS: DHPAs selectively and covalently bound to specific residues (D74, E91, H93, K133) on the hemoglobin β-1 chain, critically impairing the oxygen-carrying capacity of RBCs. MCT exposure resulted in significantly higher levels of pyrrole-hemoglobin adducts (approximately 95% binding) compared to RTS (approximately 70% binding). This higher adduction rate led to more severe systemic hypoxia, which was consistently associated with greater pulmonary arterial endothelial activation and more severe PAH in the MCT group.
CONCLUSION: The severity of PA-induced PAH is directly correlated with the degree of hemoglobin adduction and resulting hypoxia. Hemoglobin adduction and impaired oxygen transport are critical, upstream events that define the etiology of PA-induced pulmonary arterial hypertension.