Abstract
Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-β1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption.
Highlights
We evaluated the effect of SFN and sulforaphane Nacetylcysteine (SFN-NAC) on lung cell viability
As large variabilities in pharmacokinetic parameters of SFN have been reported in previous studies, we evaluated the pharmacokinetics of SFN at low doses, ranging from 0.1 to 0.5 mg/kg
Our findings revealed that SFN and SFN-NAC present similar antifibrotic activities
Summary
Pulmonary fibrosis (PF) is pathologically characterized by accumulation of fibroblastic foci, excessive matrix deposition, and aberrant remodeling that result in impaired gas exchange, diminished lung capacity, and eventually death [1,2]. Fibroblasts, the major mesenchymal cells in the lung, are activated by fibrogenic growth factors such as tissue growth factor and transforming growth factor (TGF)-β1, which promotes differentiation into myofibroblasts. Myofibroblast activation induces excessive accumulation of ECM components, which destroy the alveolar structure [3,4]. Isothiocyanates are sulfur-containing phytochemicals with the general formula RN=C=S.
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