PMID- 23179081
OWN - NLM
STAT- MEDLINE
DCOM- 20130430
LR  - 20181211
IS  - 1479-6805 (Electronic)
IS  - 0022-0795 (Linking)
VI  - 216
IP  - 3
DP  - 2013 Mar
TI  - Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic 
      receptor.
PG  - 297-305
LID - 10.1530/JOE-12-0297 [doi]
AB  - Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor 
      prognosis. Mitotane alone or in combination with other cytotoxic drugs is a 
      common therapeutic option for ACC. In addition to its adrenolytic function, 
      mitotane has been known for decades to increase the metabolic clearance of 
      glucocorticoids. It was recently shown that the tyrosine kinase inhibitor 
      sunitinib is also rapidly metabolized in patients treated with mitotane, 
      indicating that mitotane engages in clinically relevant drug interactions. 
      Although the precise mechanism of these interactions is not well understood, 
      cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both 
      glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic 
      receptor (SXR (NR1I2)) is one of the key transcriptional regulators of CYP3A4 
      gene expression in the liver and intestine. A variety of xenobiotics bind to SXR 
      and stimulate transcription of xenobiotic-response elements (XREs) located in the 
      CYP3A4 gene promoter. In this study, we evaluated the effects of mitotane on 
      SXR-mediated transcription in vitro by luciferase reporter analysis, SXR-steroid 
      receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis 
      of CYP3A4 expression, SXR knockdown, and CYP3A4 enzyme activity assays using 
      human hepatocyte-derived cells. We found that mitotane activated SXR-mediated 
      transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain 
      of SXR. Mitotane increased CYP3A4 mRNA levels, which was attenuated by SXR 
      knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We 
      conclude that mitotane can induce CYP3A4 gene expression and suggest that 
      mitotane is used cautiously due to its drug-drug interactions.
FAU - Takeshita, Akira
AU  - Takeshita A
AD  - Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical 
      Research, 2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan. coactivator@mac.com
FAU - Igarashi-Migitaka, Junko
AU  - Igarashi-Migitaka J
FAU - Koibuchi, Noriyuki
AU  - Koibuchi N
FAU - Takeuchi, Yasuhiro
AU  - Takeuchi Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130215
PL  - England
TA  - J Endocrinol
JT  - The Journal of endocrinology
JID - 0375363
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (NR1I2 protein, human)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Steroid)
RN  - 78E4J5IB5J (Mitotane)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
SB  - IM
MH  - Adult
MH  - Antineoplastic Agents, Hormonal/*pharmacology
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP3A/genetics/*metabolism
MH  - Female
MH  - Hepatocytes/*drug effects/metabolism
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Mitotane/*pharmacology
MH  - Pregnane X Receptor
MH  - Receptors, Steroid/genetics/*metabolism
EDAT- 2012/11/28 06:00
MHDA- 2013/05/01 06:00
CRDT- 2012/11/27 06:00
PHST- 2012/11/27 06:00 [entrez]
PHST- 2012/11/28 06:00 [pubmed]
PHST- 2013/05/01 06:00 [medline]
AID - JOE-12-0297 [pii]
AID - 10.1530/JOE-12-0297 [doi]
PST - epublish
SO  - J Endocrinol. 2013 Feb 15;216(3):297-305. doi: 10.1530/JOE-12-0297. Print 2013 
      Mar.