Azathioprine

Azathioprine suppresses the activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L), leading to a mitochondrial pathway of apoptosis in primary human CD4+ T lymphocytes. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. ^[1] Azathioprine-generated 6-Thio-GTP thus prevents the development of an effective immune response via blockade of Vav activity on Rac proteins. ^[2] Azathioprine (1 mM) restores ATP levels and arrests cell injury, while culture in glucose-enriched media augments ATP levels and ameliorates cell death. Azathioprine reduces viability 5-34% at day 1 and 42-92% by day 4. ^[3] Azathioprine decreases the viability of hepatocytes and induces the following events in primary culture of isolated rat hepatocytes: intracellular reduces glutathione (GSH) depletion, metabolic activity reduction, and lactate dehydrogenase release. Azathioprine effect on hepatocytes is associated with swelling and increased oxygen consumption of intact isolated rat liver mitochondria. ^[4]

Azathioprine combined with cyclosporin A and prednisolone has resulted in survival of 14 out of 15 grafts (93%), compared with 11 out of 14 (79%) in the group treated with cyclosporin A alone in mouse-rat brain xenograft. ^[5]