Mutual changes of thioredoxin and nitrosothiols during biliary cirrhosis: results from humans and cholestatic rats

Cholestasis is associated with changes in NO metabolism and thiol oxidation. Thioredoxin contributes to regulate vascular tone and intracellular redox status by cleaving nitrosothiols and maintaining -SH groups. This study investigated the changes in circulating thioredoxin and nitrosothiols and the relationship with protein sulfhydryls (PSH), hepatic concentrations, hyaluronate, and histology in patients with primary biliary cirrhosis (PBC) and in rats with bile duct ligation (BDL). PSH in erythrocytes were significantly decreased in stage III and IV PBC and at day 10 after BDL. Compared with controls, erythrocyte thioredoxin levels were higher in stage I through III PBC and lower in stage IV patients. Serum thioredoxin levels were significantly higher in PBC stages I and II and lower in stages III and IV. Serum nitrosothiols were higher in all PBC patients and inversely related to thioredoxin and hyaluronate. In rats, serum, hepatic, and mitochondrial thioredoxin had initially increased after BDL (day 1-3) and then decreased. After day 7 BDL, nitrosothiols were 10-fold increased in serum and liver, and even higher in mitochondria. In the liver, thioredoxin was inversely related to both nitrosothiols and PSH. In rats, the difference in time average changes from baseline among serum, hepatic, and erythrocyte thioredoxin suggests that most of circulating thioredoxin originates from the liver.

Our findings indicate that cholestasis is associated with significant mutual and interrelated changes between circulating and hepatic thioredoxin and nitrosothiols. The increase of hepatic, mitochondrial, and circulating nitrosothiols with ongoing cholestasis suggests an active participation of NO in both liver injury and extrahepatic changes.