To determine the persistence of the inhibition of deoxyribonucleic acid (DNA) synthesis caused by azathioprine in regenerating rat liver, labeling of DNA and accretion of total DNA and ribonucleic acid (RNA) were studied when: (1) azathioprine was discontinued after being administered during the initial phase of regeneration; (2) a second hepatectomy was carried out after an interval without azathioprine; and (3) two hepa- tectomies were performed during continuous administration of azathioprine. After stopping azathioprine for 24 hr, DNA synthesis resumed even though the mass of the liver had been restored nearly to normal by enlargement of existing cells. Following the second hepatectomy the peak of maximal DNA synthesis was delayed, but of equivalent amplitude, in both control and treated animals. The profound inhibition of DNA synthesis during 8M> days of administration of azathioprine was a result of systemic debility. Thus, the inhibitory effect of azathioprine is reversed in less than 1 day after the drug is stopped, and the proliferative potential of hepatocytes is not permanently impaired. Rational clinical use of azathioprine will probably require a dosage schedule that inhibits the immune and inflammatory responses while permitting proliferation of cells that are essential to homeostasis.
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