Pharmacokinetics andN-acetylation metabolism ofS-methyl-<scp>l</scp>-cysteine andtrans-S-1-propenyl-<scp>l</scp>-cysteine in rats and dogs

Amano, Hiroko; Kazamori, Daichi; Itoh, Kenji

doi:10.3109/00498254.2016.1144229

Cited by 20 publications

(23 citation statements)

References 17 publications

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“…Brie y, raw garlic (Allium sativum L.) was sliced into pieces, which was followed by immersing in ethanol 20-50% (v/v) and aging for more than 10 months at room temperature. S1PC, SAC and SAMC were synthesized according to the previous methods [41,42], and the purity was >99.0%.…”

Section: Methodsmentioning

confidence: 99%

S-1-Propenylcysteine Improves TNF-α-Induced Vascular Endothelial Barrier Dysfunction by Suppressing the GEF-H1/RhoA/Rac Pathway

Kunimura

Miki

Takashima

et al. 2020

Preprint

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Background: Vascular endothelial barrier function is maintained by cell-to-cell junctional proteins and contributes to vascular homeostasis. Various risk factors such as inflammation disrupt barrier function through down-regulation of these proteins and promote vascular diseases such as atherosclerosis. Previous studies have demonstrated that aged garlic extract (AGE) and its sulfur-containing constituents exert the protective effects against several vascular diseases such as atherosclerosis. In this study, we examined whether AGE and its sulfur-containing constituents improve the endothelial barrier dysfunction elicited by a pro-inflammatory cytokine, Tumor-necrosis factor-α (TNF-α), and explored their mode of action on TNF-α signaling pathway.Methods: Human umbilical vein endothelial cells (HUVECs) were treated with test substances in the presence of TNF-α for various time periods. The endothelial permeability was measured by using a transwell permeability assay. The localization of cell-to-cell junctional proteins and actin cytoskeletons were visualized by immunostaining. RhoA and Rac activities were assessed by using GTP-binding protein pulldown assay. Gene and protein expression levels of signaling molecules were analyzed by real-time PCR and western blotting, respectively. Results: We found that AGE and its major sulfur-containing constituent, S-1-propenylcysteine (S1PC), reduced hyperpermeability elicited by TNF-α in HUVECs. In addition, S1PC inhibited TNF-α-induced production of myosin light chain (MLC) kinase and inactivation of MLC phosphatase through the suppression of the Rac and RhoA signaling pathways, respectively, which resulted in the dephosphorylation of MLC2, a key factor of actin remodeling. Moreover, S1PC inhibited the phosphorylation and activation of guanine nucleotide exchange factor-H1 (GEF-H1), a common upstream key molecule and activator of Rac and RhoA. These effects of S1PC were accompanied by its ability to protect the disruption of junctional proteins on the cell-cell contact regions and the increase of actin stress fibers induced by TNF-α. Conclusions: The present study suggested that AGE and S1PC improve endothelial barrier disruption through the protection of junctional proteins on plasma membrane.

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Section: Methodsmentioning

confidence: 99%

S-1-Propenylcysteine Improves TNF-α-Induced Vascular Endothelial Barrier Dysfunction by Suppressing the GEF-H1/RhoA/Rac Pathway

Kunimura

Miki

Takashima

et al. 2020

Preprint

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“…Our previous in vitro metabolic study also demonstrated that there was a species difference in the N-acetylation metabolism of SAC, SMC, and S1PC between animals and humans, suggesting that in humans, N-acetylated metabolites are formed to a lesser extent. 18,19) Taken together, it is unlikely that the N-acetylated metabolites of SAC, SMC, and S1PC cause DDI due to CYP inhibition in humans. We also evaluated the effects of the minor metabolites (NAc-SACS, NAc-SMCS, NAc-S1PCS) on the activities of CYP isoforms and found that all the compounds had little influence on the five isoformmediated metabolisms (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…30) In any case, SAC and SMC are very unlikely to inhibit CYP3A4 activity in vivo; a preliminary pharmacokinetic study of AGE demonstrated that the maximum plasma concentration of SAC was 140 nM, 31) which is lower by three orders of magnitude than the concentration (0.1 mM) used by Greenblatt et al 17) Recently, we examined the metabolism and pharmacokinetics of SAC, SMC, and S1PC in rats and dogs and found that these compounds undergo N-acetylation and S-oxidation metabolism. 18,19) In both species, the N-acetylation is the major metabolic pathway to eliminate SAC and S1PC. In contrast, SMC is metabolized to NAc-SMC only to a small extent.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent studies revealed that three organosulfur components of AGE (SAC, SMC, S1PC) are orally well absorbed and undergo both N-acetylation and S-oxidation metabolism. 18,19) Based on these findings and considerations, we examined the effects of SAC, SMC, S1PC, along with their N-acetylated and N-acetylated/S-oxidized metabolites, on the activities of five major isoforms of human CYP (CYP1A2, 2C9, 2C19, …”

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confidence: 99%

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Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities

Amano

Kazamori

Itoh

2016

Biological & Pharmaceutical Bulletin

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Three major organosulfur compounds of aged garlic extract, S-allyl-L-cysteine (SAC), S-methyl-Lcysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC), were examined for their effects on the activities of five major isoforms of human CYP enzymes: CYP1A2, 2C9, 2C19, 2D6, and 3A4. The metabolite formation from probe substrates for the CYP isoforms was examined in human liver microsomes in the presence of organosulfur compounds at 0.01-1 mM by using liquid chromatography-tandem mass spectrometry (LC-MS/ MS) analysis. Allicin, a major component of garlic, inhibited CYP1A2 and CYP3A4 activity by 21-45% at 0.03 mM. In contrast, a CYP2C9-catalyzed reaction was enhanced by up to 1.9 times in the presence of allicin at 0.003-0.3 mM. SAC, SMC, and S1PC had no effect on the activities of the five isoforms, except that S1PC inhibited CYP3A4-catalyzed midazolam 1′-hydroxylation by 31% at 1 mM. The N-acetylated metabolites of the three compounds inhibited the activities of several isoforms to a varying degree at 1 mM. N-Acetyl-Sallyl-L-cysteine and N-acetyl-S-methyl-L-cysteine inhibited the reactions catalyzed by CYP2D6 and CYP1A2, by 19 and 26%, respectively, whereas trans-N-acetyl-S-1-propenyl-L-cysteine showed weak to moderate inhibition (19-49%) of CYP1A2, 2C19, 2D6, and 3A4 activities. On the other hand, both the N-acetylated and Soxidized metabolites of SAC, SMC, and S1PC had little effect on the reactions catalyzed by the five isoforms. These results indicated that SAC, SMC, and S1PC have little potential to cause drug-drug interaction due to CYP inhibition or activation in vivo, as judged by their minimal effects (IC 50 >1 mM) on the activities of five major isoforms of human CYP in vitro.Key words organosulfur compound; cytochrome P450 inhibition; drug-drug interaction; garlic Garlic (Allium sativum L.) has been widely consumed since ancient times and its health benefits as a supplementary medicine have been well recognized.1) Recently, the increased use of herbal medicines has raised concerns about potential interactions with prescription medications. Of particular concern are drug-drug interactions (DDIs) caused by the inhibition or induction of drug-metabolizing enzymes, in particular, CYP enzymes. 2-4)Aged garlic extract (AGE) is a unique garlic product manufactured through a long extraction process from raw garlic and its multiple pharmacologic effects have been demonstrated in several clinical studies. [5][6][7][8] This extraction process leads to the reduction of odorous, acidic, and irritating compounds found in fresh garlic and the enrichment of water-soluble organosulfur components in AGE, such as S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC)9) (Fig. 1). SAC is recognized as an active key component of AGE, and its favorable effects have been demonstrated, including a cholesterol-lowering effect, 10) an antioxidative effect, 11) and an anticancer effect. 12) There has been limited study on the biological and pharmacologic activities of S1PC; however, its immun...

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“…AGE has been shown to exert immuno-enhancing and anti-inflammatory effects (1)(2)(3)(4)(5). S-1-propenylcysteine (S1PC), a major characteristic sulfur compound in AGE, which exhibits good oral bioavailability in rats and canines (6), has been shown to exert several beneficial effects, such as immunoregulatory, anti-hypertensive and blood flow-promoting effects (7)(8)(9)(10). Moreover, in our previous recent studies, it was indicated that S1PC promoted intestinal immunoglobulin A (IgA) production and inhibited lipopolysaccharide (LPS)-induced IL-6 production (7,10).…”

Section: Introductionmentioning

confidence: 99%

Regulation of immune response by S‑1‑propenylcysteine through autophagy‑mediated protein degradation (Review)

et al. 2019

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Autophagy is a key event in cellular recycling processes due to its involvement in the intracellular degradation of proteins. It has been demonstrated that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in aged garlic extract, induces the activation of autophagy. S1PC degrades the adaptor protein myeloid differentiation response protein 88 (MyD88) of downstream of Toll-like receptor (TLR) by activating autophagy in vitro and in vivo. The degradation of MyD88 inhibits the TLR signaling pathway, including the phosphorylation of interleukin 1 receptor associated kinase 4 (IRAK4) and nuclear factor (NF)-κB p65 in vitro, and eventually leads to the inhibition of interleukin (IL)-6 production in vitro and CC motif chemokine ligand 2 (Ccl2) mRNA expression in vivo. S1PC also increases the level of intestinal immunoglobulin A (IgA) and the number of IgA-producing cells in Peyer's patches in vivo. In addition, S1PC triggers the mRNA expression of X-box binding protein 1 (Xbp1), an inducer of IgA-producing cell differentiation via the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and the degradation of paired box protein 5 (Pax5), a suppressor of Xbp1 mRNA expression. The present review summarizes the mechanisms through which the activation of autophagy by S1PC modulates the immune response. Contents 1. Introduction 2. S1PC induces the activation of autophagy 3. Anti-inflammatory effects of S1PC 4. Immuno-enhancing effects of S1PC 5. Conclusions and future perspectives Regulation of immune response by S-1-propenylcysteine through autophagy-mediated protein degradation (Review)

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Pharmacokinetics andN-acetylation metabolism ofS-methyl-l-cysteine andtrans-S-1-propenyl-l-cysteine in rats and dogs

Cited by 20 publications

References 17 publications

S-1-Propenylcysteine Improves TNF-α-Induced Vascular Endothelial Barrier Dysfunction by Suppressing the GEF-H1/RhoA/Rac Pathway

S-1-Propenylcysteine Improves TNF-α-Induced Vascular Endothelial Barrier Dysfunction by Suppressing the GEF-H1/RhoA/Rac Pathway

Evaluation of the Effects of <i>S</i>-Allyl-L-cysteine, <i>S</i>-Methyl-L-cysteine, <i>trans</i>-<i>S</i>-1-Propenyl-L-cysteine, and Their <i>N</i>-Acetylated and <i>S</i>-Oxidized Metabolites on Human CYP Activities

Regulation of immune response by S‑1‑propenylcysteine through autophagy‑mediated protein degradation (Review)

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