Hydrogen sulfide (H2S) is a crucial signaling molecule involved in regulating inflammation, oxidative stress, and metabolism. S-propargyl-cysteine (SPRC) modulates endogenous H2S production pathways by influencing relevant enzymes, presenting a potential therapeutic approach for conditions associated with abnormal sulfide levels. This study investigated the safety and pharmacokinetic properties of SPRC in a Good Laboratory Practice 28-day oral toxicity study in rats, including safety pharmacology and gene toxicity assessments. SPRC exhibited favorable pharmacokinetic characteristics and safety margins, with a No Observed Adverse Effect Level (NOAEL) of 37.5 mg/kg, translating to an estimated 8.5-fold therapeutic window. These initial toxicology findings, coupled with SPRC’s pharmacological effects on the sulfide signaling axis, support its progression to first-in-human clinical trials for further benefit risk evaluation. The promising safety and pharmacokinetic profile of SPRC underscores its therapeutic potential and justifies additional clinical investigation for disorders linked to aberrant sulfide signaling. To comprehensively assess the therapeutic utility of SPRC, further preclinical safety evaluations and early phase clinical studies are warranted. These investigations will provide insights into SPRC’s potential to address unmet medical needs in various disease areas related to disrupted sulfur metabolism and hydrogen sulfide biology.
References
[1]
Kimura, H. (2010) Hydrogen Sulfide as a Physiological Mediator: Its Function and Therapeutic Applications. FoliaPharmacologicaJaponica, 136, 335-339. https://doi.org/10.1254/fpj.136.335
[2]
Kimura, H. (2024) Hydrogen Sulfide (H2S)/Polysulfides (H2Sn) Signalling and TRPA1 Channels Modification on Sulfur Metabolism. Biomolecules, 14, Article 129. https://doi.org/10.3390/biom14010129
[3]
Li, L., Rose, P. and Moore, P.K. (2011) Hydrogen Sulfide and Cell Signaling. AnnualReviewofPharmacologyandToxicology, 51, 169-187. https://doi.org/10.1146/annurev-pharmtox-010510-100505
[4]
Wang, R., Cai, J., Chen, K., Zhu, M., Li, Z., Liu, H., et al. (2022) STAT3-NAV2 Axis as a New Therapeutic Target for Rheumatoid Arthritis via Activating SSH1L/Cofilin-1 Signaling Pathway. SignalTransductionandTargetedTherapy, 7, Article No. 209. https://doi.org/10.1038/s41392-022-01050-7
[5]
Zhu, M., Ding, Q., Lin, Z., Fu, R., Zhang, F., Li, Z., et al. (2023) New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect. Biomolecules, 13, Article 766. https://doi.org/10.3390/biom13050766
[6]
Ma, G., Zhang, L., Zhang, P., Bao, X., Zhou, N., Shi, Q., et al. (2014) Physicochemical Characteristics and Gastrointestinal Absorption Behaviors of s-Propargyl-Cysteine, a Potential New Drug Candidate for Cardiovascular Protection and Antitumor Treatment. Xenobiotica, 45, 322-334. https://doi.org/10.3109/00498254.2014.980369
[7]
Wen, Y. and Zhu, Y. (2015) The Pharmacological Effects of S-Propargyl-Cysteine, a Novel Endogenous H2S-Producing Compound. In: Moore, P. and Whiteman, M., Eds., Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide, Springer, 325-336. https://doi.org/10.1007/978-3-319-18144-8_16
Li, L., Hsu, A. and Moore, P.K. (2009) Actions and Interactions of Nitric Oxide, Carbon Monoxide and Hydrogen Sulphide in the Cardiovascular System and in Inflammation—A Tale of Three Gases! Pharmacology&Therapeutics, 123, 386-400. https://doi.org/10.1016/j.pharmthera.2009.05.005
[10]
Zaorska, E., Tomasova, L., Koszelewski, D., Ostaszewski, R. and Ufnal, M. (2020) Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors. Biomolecules, 10, Article 323. https://doi.org/10.3390/biom10020323
[11]
Andrés, C.M.C., Pérez de la Lastra, J.M., Andrés Juan, C., Plou, F.J. and Pérez-Lebeña, E. (2023) Chemistry of Hydrogen Sulfide—Pathological and Physiological Functions in Mammalian Cells. Cells, 12, Article 2684. https://doi.org/10.3390/cells12232684
[12]
Li, W., Ma, F., Zhang, L., Huang, Y., Li, X., Zhang, A., et al. (2016) S‐Propargyl-Cysteine Exerts a Novel Protective Effect on Methionine and Choline Deficient Diet-Induced Fatty Liver via Akt/Nrf2/HO‐1 Pathway. OxidativeMedicineandCellularLongevity, 2016, Article ID: 4690857. https://doi.org/10.1155/2016/4690857
[13]
Cao, X., Ding, L., Xie, Z., Yang, Y., Whiteman, M., Moore, P.K., et al. (2019) A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer? Antioxidants&RedoxSignaling, 31, 1-38. https://doi.org/10.1089/ars.2017.7058
[14]
Wang, W., Ge, T., Chen, X., Mao, Y. and Zhu, Y. (2020) Advances in the Protective Mechanism of NO, H2S, and H2 in Myocardial Ischemic Injury. FrontiersinCardiovascularMedicine, 7, Article 588206. https://doi.org/10.3389/fcvm.2020.588206
[15]
Wang, Y., Ngowi, E.E., Wang, D., Qi, H., Jing, M., Zhang, Y., et al. (2021) The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases. InternationalJournalofMolecularSciences, 22, Article 2194. https://doi.org/10.3390/ijms22042194
[16]
Yu, Y., Wang, Z., Ding, Q., Yu, X., Yang, Q., Wang, R., et al. (2021) The Preparation of a Novel Poly(Lactic Acid)-Based Sustained H2S Releasing Microsphere for Rheumatoid Arthritis Alleviation. Pharmaceutics, 13, Article 742. https://doi.org/10.3390/pharmaceutics13050742
Zhu, C., Liu, Q., Li, X., Wei, R., Ge, T., Zheng, X., et al. (2022) Hydrogen Sulfide: A New Therapeutic Target in Vascular Diseases. FrontiersinEndocrinology, 13, Article 934231. https://doi.org/10.3389/fendo.2022.934231
[19]
Zheng, Y., Liu, H., Ma, G., Yang, P., Zhang, L., Gu, Y., et al. (2011) Determination of S-Propargyl-Cysteine in Rat Plasma by Mixed-Mode Reversed-Phase and Cation-Exchange HPLC–MS/MS Method and Its Application to Pharmacokinetic Studies. JournalofPharmaceuticalandBiomedicalAnalysis, 54, 1187-1191. https://doi.org/10.1016/j.jpba.2010.11.027
[20]
Zheng, Y., Zhu, J., Ma, G., Zhu, Q., Yang, P., Tan, B., et al. (2012) Preclinical Assessment of the Distribution, Metabolism, and Excretion of S-Propargyl-Cysteine, a Novel H2S Donor, in Sprague-Dawley Rats. ActaPharmacologicaSinica, 33, 839-844. https://doi.org/10.1038/aps.2012.15
[21]
Zheng, Y., Xu, J., Ma, G., Zhang, J., Zhu, Q., Liu, H., et al. (2011) Bioavailability and Pharmacokinetics of S-Propargyl-L-Cysteine, a Novel Cardioprotective Agent, after Single and Multiple Doses in Beagle Dogs. Xenobiotica, 42, 304-309. https://doi.org/10.3109/00498254.2011.617848
[22]
Nair, A. and Jacob, S. (2016) A Simple Practice Guide for Dose Conversion between Animals and Human. JournalofBasicandClinicalPharmacy, 7, 27-31. https://doi.org/10.4103/0976-0105.177703
[23]
Pan, L., Liu, X., Gong, Q. and Zhu, Y. (2011) S-Propargyl-Cysteine (SPRC) Attenuated Lipopolysaccharide-Induced Inflammatory Response in H9C2 Cells Involved in a Hydrogen Sulfide-Dependent Mechanism. Amino Acids, 41, 205-215. https://doi.org/10.1007/s00726-011-0834-1
[24]
Li, P., Li, Z.M., Zhang, B.S., et al. (2024) S-Propargyl-Cysteine Promotes the Stability of Atherosclerotic Plaque via Maintaining Vascular Muscle Contractile Phenotype. Frontiers in Cell and Developmental Biology, 11, Article 1291170. https://doi.org/10.3389/fcell.2023.1291170
[25]
Blank, M., et al. (2009) Review of Qualification Data for Biomarkers of Nephrotoxicity Submitted by the Predictive Safety Testing Consortium. https://www.fda.gov/media/87781/download
[26]
Kashfi, K. and Olson, K.R. (2013) Biology and Therapeutic Potential of Hydrogen Sulfide and Hydrogen Sulfide-Releasing Chimeras. BiochemicalPharmacology, 85, 689-703. https://doi.org/10.1016/j.bcp.2012.10.019
[27]
Heimbach, T., Lakshminarayana, S.B., Hu, W. and He, H. (2009) Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using in Vitro and Preclinical in Vivo Data. TheAAPSJournal, 11, 602-614. https://doi.org/10.1208/s12248-009-9136-x
