Perturbation of S-Adenosylhomocysteine (SAH) and S-Adenosylmethionine (SAM) Levels Following 2’-Deoxycoformycin (dCf) and 2’-Deoxyadenosine (AdR) Administration

Abstract

In mice treated with the adenosine deaminase inhibitor dCf (0.27mg/kg daily x 5) in combination with AdR (267mg/kg daily x 5), death was attributable to acute hepatic dysfunction (Paine et al, Cancer Treat. Rep. 65: 259, 1981). The dose of AdR was the primary determinant of hepatotoxicity. Preliminary investigations demonstrated dramatic increases in liver SAH levels suggesting that inhibition of SAH hydrolase by AdR may be the primary biochemical lesion (Renshaw et al, J. Clin. Chem. Clin. Biochem. 20: 409, 1982). Elevated SAH levels with depressed SAM:SAH ratios will result in inhibition of transmethylation reactions essential to normal tissue function and survival. Further investigations have revealed that while SAH and SAM levels and their ratios normalise by 24 hours after each days’ treatment for the first 2 days no such recovery is demonstrated thereafter. Elevations of liver SAH levels are such that efflux of SAH from the liver into the plasma occurs with subsequent excretion of substantial quantities of SAH in the urine. The “trapping” of adenosine in SAH may contribute to the reduced levels of ATP demonstrated in vivo following dCf treatment which in conjunction with elevated dATP levels may result in compromised energy metabolism (Siaw et al, Proc. Natl. Acad. Sci. USA 77: 6157, 1980). It is suggested that the monitoring of plasma and/or urinary SAH levels during dCf treatment of patients may prove useful for the prediction of systemic toxicity.