S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver.

S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, as well as in some hepatic mtDNA depletion syndromes, whose pathogenesis of liver dysfunction is still poorly established. Therefore, in the present work, we investigated the effects of S-adenosylmethionine (AdoMet) on mitochondrial functions and redox homeostasis in rat liver. AdoMet decreased mitochondrial membrane potential and Ca2+ retention capacity, and these effects were fully prevented by cyclosporin A and ADP, indicating mitochondrial permeability transition (mPT) induction. It was also verified that the thiol-alkylating agent NEM prevented AdoMet-induced ΔΨm dissipation, implying a role for thiol oxidation in the mPT pore opening. AdoMet also increased ROS production and provoked protein and lipid oxidation. Furthermore, AdoMet reduced GSH levels and the activities of aconitase and α-ketoglutarate dehydrogenase. Free radical scavengers attenuated AdoMet effects on lipid peroxidation and GSH levels, supporting a role of ROS in these effects. It is therefore presumed that disturbance of mitochondrial functions associated with mPT and redox unbalance may represent relevant pathomechanisms of liver damage provoked by AdoMet in disorders in which this metabolite accumulates.

Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis.

A double-blind, randomized, 84-day controlled clinical trial was carried out to compare orally administered S-adenosylmethionine (SAMe) (1,200 mg per day) with oral piroxicam therapy (20 mg per day) in the management of unilateral knee osteoarthritis. The ability of each drug to maintain the results achieved at the end of the treatment period was also evaluated during a 56-day follow-up period. Forty-five patients completed the study, 22 in the SAMe group and 23 in the piroxicam group. Both SAMe and piroxicam proved effective in inducing a significant improvement in the total pain score after 28 days of treatment. With regard to the other clinical parameters (i.e., morning stiffness, the distance walked before the onset of pain, active and passive motility), improvement started from about Day 56 in both groups. No significant difference was found between the two treatments in terms of efficacy and tolerability. Patients treated with SAMe maintained clinical improvement achieved at the end of treatment longer than did patients receiving piroxicam.