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Alanine Aminotransferase Regulation by Androgens in Non-hepatic Tissues

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Abstract

Purpose

Alanine amino-transferases (ALTs) play a crucial role in drug development as a surrogate marker of liver injury where elevations in serum ALT activity are used to diagnose drug-induced liver damage. Two ALT isoforms have been characterized with disparate but overlapping tissue expression. ALT1 is primarily expressed in live; ALT2 is found in muscle and prostate tissues. We investigate ALT gene expression in diverse rodent tissues following administration of the steroidal androgen receptor (AR) agonist dihydrotestosterone and a novel tissue selective nonsteroidal agonist S-23.

Methods

Putative AR regulation of ALT expression was determined in silico by an orthologous promoter androgen response element (ARE) search. Regulation was evaluated by transient transfection of ALT promoter region constructs and qRT-PCR experiments in cultured cells and in tissues following androgen administration.

Results

Several putative AREs were found in the proximal promoter regions of ALT1 and ALT2. AREs in ALT2 but not ALT1 were capable of AR-mediated transcription. ALT2 expression was affected by castration and androgen administration in muscle and prostate but not liver tissues.

Conclusions

Androgen action in non-hepatic tissues, as opposed to xenobiotic toxicity alone, may contribute to increases in serum ALT activity following androgen administration.

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Acknowledgments & Disclosures

We thank Drs. Jeffrey Kearbey and Amanda Jones for their discussions and help with the in vivo studies and Dr. Victor Jin for sharing MatInd code. Also Terry Costello, Katie Kail and Stacey Lindsey were invaluable in the implementation of the in vivo work.

All authors are employees of GTx, Inc. and hold stock options in the company. D.D.M. and J.T.D. are inventors on SARM patents and may receive invention royalties from the University of Tennessee Research Foundation.

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Authors and Affiliations

  1. Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, Tennessee, 38163, USA

    Christopher C. Coss, Matt Bauler, Ramesh Narayanan, Duane D. Miller & James T. Dalton

Authors
  1. Christopher C. Coss
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  2. Matt Bauler
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  3. Ramesh Narayanan
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  4. Duane D. Miller
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  5. James T. Dalton
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Corresponding author

Correspondence to James T. Dalton.

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Coss, C.C., Bauler, M., Narayanan, R. et al. Alanine Aminotransferase Regulation by Androgens in Non-hepatic Tissues. Pharm Res 29, 1046–1056 (2012). https://doi.org/10.1007/s11095-011-0649-5

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  • DOI: https://doi.org/10.1007/s11095-011-0649-5

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