ICEECE2012 Poster Presentations Endocrine tumours and neoplasia (112 abstracts)
Urinary steroid profiling demonstrates induction of CYP3A4 and inhibition of 5alpha-reductase by mitotane treatment for adrenocortical carcinoma
A. Taylor 1 , V. Chortis 1 , P. Schneider 1 , J. Tomlinson 1 , B. Hughes 1 , D. Smith 1 , R. Libe 2 , B. Allolio 3 , X. Bertagna 2 , J. Bertherat 2 , F. Beuschlein 7 , M. Fassnacht 3 , M. Mannelli 4 , F. Mantero 5 , G. Opocher 5 , E. Porfiri 1 , M. Quinkler 3 , M. Terzolo 6 , C. Shackelton 1 , P. Stewart 1 , S. Hanher 3 & W. Arlt 1
Ludwig-Maximilians University, Florence, Italy.
Mitotane (o,p’DDD) is commonly used for the treatment of adrenocortical carcinoma (ACC), both for advanced disease and in the adjuvant setting. Mitotane induces adrenal insufficiency but specific effects on steroidogenic enzymes are unknown.
We investigated 24-h urinary steroid metabolite excretion in ACC patients on adjuvant mitotane (AD) or mitotane for metastatic disease (MET). We compared samples collected before mitotane treatment (BEFORE; MET n=57; AD n=12) to samples collected after 3–4 months of treatment when therapeutic range plasma mitotane levels had been achieved (AFTER; MET n=47; AD n=11). Steroid metabolite excretion was analysed by gas chromatography mass-spectrometry, facilitating the selective identification and quantification of 32 steroid metabolites. We also calculated steroid substrate over product ratios to diagnose impairment of distinct steroid converting enzymes including 5alpha-reductase (5alpha-tetrahydrocortisol/tetrahydrocortisol; 5αTHF/THF) and CYP3A4 (6beta-hydroxycortisol/cortisol; 6βOHF/F).
We found a strong inhibition of 5alpha-reductase activity by mitotane (5αTHF/THF: MET-before 3.6±6.3 vs. MET-after 0.05±0.07; AD-before 0.5±0.4 vs. AD-after 0.02±0.01; all P<0.001). The extent of this inhibition was comparable to patients treated with the known 5alpha-reductase type 2 inhibitor finasteride (5αTHF/THF 0.02±0.006; n=5) and patients with inactivating 5alpha-reductase type 2 mutations (5αTHF/THF 0.04±0.03 n=23). We also found evidence of a strong induction of the major drug and steroid-metabolising enzyme CYP3A4 (6βOHF/F: MET-before 2.1±3.6 vs. MET-after 20.5±9.7; AD-before 2.4±0.8 vs. AD-after 30.2±5.1; all P<0.001). 6βOHF represented only 3.4% (1–4%) of total cortisol metabolite excretion before mitotane, which increased hugely to 54% (39–70%) on mitotane (P<0.001) irrespective of tumour load.
Longitudinal data from patients receiving adjuvant mitotane (n=4) demonstrated lasting effects on CYP3A4 and 5alpha-reductase activities, with restoration to normal only after 12 months off treatment. CYP3A4 induction results in rapid inactivation of hydrocortisone replacement, explaining the increased hydrocortisone dose requirements in mitotane-induced adrenal insufficiency.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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