Mitotane is a unique antineoplastic agent used solely in the therapy of metastatic, unresectable adrenocortical carcinoma. Mitotane has been associated with a high rate of serum enzyme elevation during therapy, but has had limited clinical use and has not been linked to instances of clinically apparent acute liver injury.


Mitotane (mye' toe tane) is an isomer of DDT (dichloro-diphenyl-trichloroethane) which was found to cause adrenal atrophy in dogs and was later developed as an antineoplastic agent for advanced or metastatic adrenocortical carcinoma. Mitotane is directly cytotoxic to adrenal tissue and appears to act by inhibition of sterol-O-acyl-transferase (SOAT) activity which blocks the esterification of cholesterol. Cholesterol is the precursor of adrenocortical hormones and it accumulates in adrenocortical cells. The prevention of esterification causes an excess of free cholesterol and other fatty acids which are is toxic to the hormone producing adrenal cells. Treatment with mitotane regularly causes a decrease in corticosteroid synthesis and can result in adrenal insufficiency and Addisonian crisis. Mitotane was approved for use in the chemotherapy of advanced adrenal carcinoma in the United States in 1970. It is available as tablets of 500 mg under the brand name Lysodren. The typical initial dose is 2 to 6 grams daily in 3 to 4 divided doses, which can be increased to achieve a blood concentration of 14 to 20 mg/L. Side effects of mitotane therapy are common and can include anorexia, nausea, vomiting, diarrhea, depression, dizziness, decreased memory and concentration, rash, gynecomastia, arthralgia and leukopenia. Potentially severe adverse events include adrenal insufficiency and crisis.


Serum aminotransferase elevations occur in up to half of patients on conventional doses of mitotane therapy, but elevations above 5 times the upper limit of normal are uncommon (<1%). There have been no individual published case reports of clinically apparent liver injury attributed to mitotane, but its general use has been limited, as adrenocortical carcinoma is rare. Furthermore, the nonspecific side effects of mitotane therapy are often dose limiting and may be mediated, at least in part, by hepatic dysfunction or injury perhaps due to the same lipotoxicity that accounts for adrenocortical injury.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

While hepatotoxicity from mitotane may be rare, it is likely due to direct hepatotoxicity. Mitotane is extensively metabolized in the liver via the microsomal enzyme system (predominantly 2C9), and production of a toxic or immunogenic intermediate may trigger liver injury.

Outcome and Management

The severity of the liver injury linked to mitotane therapy has been generally mild, transient and without symptoms or jaundice. Mitotane has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between mitotane and other antineoplastic agents.

Drug Class: Antineoplastic Agents



Mitotane – Lysodren®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 19 February 2020

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    (Expert review of hepatotoxicity of cancer chemotherapeutic agents published in 1999; mentions that mitotane can cause elevations in serum aminotransferase levels).
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