Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Biochem Pharmacol. 2020 Feb;172:113781. doi: 10.1016/j.bcp.2019.113781. Epub 2019 Dec 27.

Profiling of anabolic androgenic steroids and selective androgen receptor modulators for interference with adrenal steroidogenesis.

Author information

1
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: melanie.patt@unibas.ch.
2
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: katharina.beck@unibas.ch.
3
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: tobias.dimarco@outlook.com.
4
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: m.jaeger@unibas.ch.
5
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 4, Switzerland. Electronic address: victor.gonzalez@unige.ch.
6
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 4, Switzerland. Electronic address: julien.boccard@unige.ch.
7
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 4, Switzerland. Electronic address: serge.rudaz@unige.ch.
8
Department Drug Design and Optimization (DDOP), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123 Saarbrücken, Germany; Department of Pharmaceutical and Medicinal Chemistry, Universitätscampus C2.3, 66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
9
Department of Pharmaceutical and Medicinal Chemistry, Universitätscampus C2.3, 66123 Saarbrücken, Germany. Electronic address: mohamed.rezk87@hotmail.com.
10
Department of Pharmaceutical and Medicinal Chemistry, Universitätscampus C2.3, 66123 Saarbrücken, Germany. Electronic address: vankoppen@elexopharm.de.
11
Lipomed AG, Fabrikmattenweg 4, 4144 Arlesheim, Switzerland. Electronic address: grill78@web.de.
12
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

Abstract

Anabolic-androgenic steroids (AAS) are testosterone derivatives developed for steroid-replacement and treatment of debilitating conditions. They are widely used by athletes in elite sports and bodybuilding due to their muscle-building and performance-enhancing properties. Excessive AAS use is associated with cardiovascular diseases, mood changes, endocrine and metabolic disorders; however, the underlying mechanisms remain unknown. Selective androgen receptor modulators (SARMs) aim to reduce adverse androgenic effects, while maximizing anabolic effects. This study assessed potential steroidogenic disturbances of 19 AAS and 3 SARMs in human adrenocortical carcinoma H295R cells, comparing basal and forskolin-activated states by mass spectrometry-based quantification of nine major adrenal steroids. Mesterolone, mestanolone and methenolone increased mineralocorticoid but decreased adrenal androgen production, indicating CYP17A1 dysfunction. Cell-free activity assays failed to detect direct CYP17A1 inhibition, supported by molecular modeling. The mRNA expression levels of 3β-HSD2, CYP17A1, CYP21A2, CYP11B1 and CYP11B2 were unaffected, suggesting indirect inhibition involving post-translational modification and/or impaired protein stability. Clostebol and oxymetholone decreased corticosteroid but increased dehydroepiandrosterone biosynthesis in H295R cells, suggesting CYP21A2 inhibition, sustained by molecular modeling. These AAS did not affect the expression of key steroidogenic genes. None of the SARMs tested interfered with steroidogenesis. The chosen approach allowed the grouping of AAS according to their steroidogenic-disrupting effects and provided initial mechanistic information. Mesterolone, mestanolone and methenolone potentially promote hypertension and cardiovascular diseases via excessive mineralocorticoid biosynthesis. Clostebol and oxymetholone might cause metabolic disturbances by suppressing corticosteroid production, resulting in adrenal hyperplasia. The non-steroidal SARMs exhibit an improved safety profile and represent a preferred therapeutic option.

KEYWORDS:

Adrenal gland; Cardiovascular disease; H295R; Hypertension; Steroid biosynthesis

PMID:
31884045
DOI:
10.1016/j.bcp.2019.113781

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center