Alleviation of paraquat-induced oxidative lung injury by betaine via regulation of sulfur-containing amino acid metabolism despite the lack of betaine-homocysteine methyltransferase (BHMT) in the lung

Abstract

Betaine is a methyl donor utilized in regeneration of methionine from homocysteine in a metabolic reaction catalyzed by betaine-homocysteine methyltransferase (BHMT), an enzyme mostly localized in the liver. However, we recently showed that the metabolism of sulfur-containing amino acids in the kidney was also influenced by betaine, which is attributable to elevation of renal methionine availability resulting from an increase in its supply through blood. In this study we investigated the change in pulmonary sulfur-containing amino acid metabolism by betaine and its potential beneficial effect on paraquat (PQ)-induced lung injury. Male rats were provided with betaine for 2 weeks prior to an intratracheal instillation of PQ (0.3 mg/500 μl kg⁻¹). Two weeks after PQ exposure, histopathological assessment revealed severe fibrotic lesions accompanied with elevation of 4-hydroxyproline in the lung, which were all prevented effectively by betaine supplementation. PQ-induced DNA fragmentation in lymphocytes, reduction of oxidant scavenging capacity, expression of heme oxygenase 1 and inducible nitric oxide synthase in the lung, and elevation of serum transforming growth factor beta 1 were also inhibited. PQ instillation increased cysteine, but depleted glutathione in the lung. Betaine supplementation before PQ exposure suppressed the cysteine accumulation and increased the glutathione synthesis. The polyamine synthesis, which requires decarboxylated S-adenosylmethionine as a substrate, was also increased significantly. The results suggest that betaine may enhance pulmonary antioxidant capacity by modulating the metabolism of sulfur-containing amino acids and related substances despite the lack of BHMT in the lung.