Abstract
γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5 mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of > 370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 196-202 |
| Number of pages | 7 |
| Journal | Toxicology in Vitro |
| Volume | 40 |
| DOIs | |
| State | Published - Apr 1 2017 |
| Externally published | Yes |
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Keywords
- Apoptosis
- Cytochrome P-450 (CYP)
- Cytotoxicity
- Gene expression
- HepG2 cells
- Microsomal CYPs
- Mitochondrial function
- Primary human hepatocytes
- PXR
- Xenobiotic receptor induction
ASJC Scopus subject areas
- Toxicology
Cite this
In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding. / Vogel, K. R.; Ainslie, G. R.; Roullet, Jean-Baptiste; McConnell, A.; Gibson, K. M.
In: Toxicology in Vitro, Vol. 40, 01.04.2017, p. 196-202.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding
AU - Vogel, K. R.
AU - Ainslie, G. R.
AU - Roullet, Jean-Baptiste
AU - McConnell, A.
AU - Gibson, K. M.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5 mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of > 370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382.
AB - γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5 mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of > 370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382.
KW - Apoptosis
KW - Cytochrome P-450 (CYP)
KW - Cytotoxicity
KW - Gene expression
KW - HepG2 cells
KW - Microsomal CYPs
KW - Mitochondrial function
KW - Primary human hepatocytes
KW - PXR
KW - Xenobiotic receptor induction
UR - http://www.scopus.com/inward/record.url?scp=85010782766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85010782766&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2017.01.013
DO - 10.1016/j.tiv.2017.01.013
M3 - Article
C2 - 28119166
AN - SCOPUS:85010782766
VL - 40
SP - 196
EP - 202
JO - Toxicology in Vitro
JF - Toxicology in Vitro
SN - 0887-2333
ER -