Endocrine Abstracts (2012) 28 OC5.4

Steroid metabolomics in adrenocortical carcinoma reveals mitotane as an inducer of CYP3A4 and an inhibitor of 5alpha-reductase activity with major implications for drug metabolism and hydrocortisone replacement

Vasileios Chortis1, Angela Taylor1, Petra Schneider1, Jeremy Tomlinson1, Beverly Hughes1, David Smith4, Emilio Porfiri3, Cedric Shackleton1, Paul Stewart1,2 & Wiebke Arlt1,2

1Centre for Endocrinology Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham, United Kingdom; 2European Network for the Study of Adrenal Tumours (ENS@T), University of Birmingham, Birmingham, United Kingdom; 3School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; 4School of Mathematics, University of Birmingham, Birmingham, United Kingdom.

Mitotane (o,p’DDD) is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumour. Mitotane is considered an adrenolytic substance, but no information is available regarding distinct steroidogenic effects. Here we carried out steroid metabolomics by gas chromatography/mass spectrometry in 24-hour urine samples from 106 patients with ACC and with samples collected before and after mitotane initiation. Samples on mitotane were collected when therapeutic plasma mitotane levels had been achieved. Results revealed mitotane as a strong inducer of the major drug-metabolising enzyme CYP3A4, as reflected by significantly increased 6β-hydroxycortisol/cortisol ratios comparing steroid profiles before and after mitotane (all P<0.001). 6β-OH-cortisol represented a median of 1.8% (IQR 1-4%) of total cortisol metabolites prior to mitotane, which rose to 56% (IQR 39-71%) whilst on mitotane treatment. We also found that mitotane acted as a strong inhibitor of 5α-reductase activity, reflected by a highly significant decrease in the ratios of 5α-tetrahydrocortisol/tetrahydrocortisol and androsterone/etiocholanolone (all P<0.001). The inhibitory effect on 5α-reductase reflected by these ratios was similar to that observed for the established 5α-reductase inhibitor finasteride (compared to five 24-hour urine samples from finasteride-treated patients). Longitudinal data showed a lasting effect of mitotane on CYP3A4 and 5α-reductase activities with restoration to normal not earlier than 12 months after treatment cessation. In addition to these two distinct effects, mitotane significantly down regulated overall steroid output. The induction of CYP3A4 by mitotane will result in rapid inactivation of hydrocortisone replacement in mitotane-treated patients and will also impact significantly on the metabolism and thus the action of a multitude of drugs (e.g. cytotoxic drugs such as sunitinib). The therapeutic potential of mitotane as a 5α-reductase inhibitor for example in the context of testicular Leydig cell carcinoma or prostate cancer deserves further exploration.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by the Medical Research Council (grant numbers G0801473).