Abstract
The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K2(20)), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to the photoinstability and phototoxicity of MK-4. This study aimed to evaluate the potential of ester prodrugs of MKH for its delivery into the skin to avoid the abovementioned issues. The ester prodrugs, MKH 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG) and MKH 1,4-bis-hemisuccinate (MKH-SUC), were prepared using our previously reported methods. Photostability was determined under artificial sunlight and multi-wavelength light irradiation, phototoxicity was determined by intracellular ROS formation and cell viability of UVA-irradiated human epidermal keratinocyte cells (HaCaT), and delivery of MKH into HaCaT cells was assessed by measuring menaquinone-4 epoxide (MKO) levels. MKH prodrugs showed higher photostability than MK-4. Although MK-4 induced cellular ROS and reduced cell viability after UVA irradiation, MKH prodrugs did not affect either ROS generation or cell viability. MKH prodrugs enhanced intracellular MKO, indicating effective delivery of MKH and subsequent carboxylation activity. In conclusion, these MKH prodrugs show potential for the delivery of MKH into the skin without photoinstability and phototoxicity.
Highlights
IntroductionMenahydroquinone-4 (MKH), the fully reduced and active form of MK-4, is a cofactor for γ-glutamyl carboxylase (GGCX), which catalyzes the post-transcriptional carboxylation of vitamin K-dependent proteins
Menaquinone-4 (MK-4) or vitamin K2(20) is an important vitamin K compound used clinically.Menahydroquinone-4 (MKH), the fully reduced and active form of MK-4, is a cofactor for γ-glutamyl carboxylase (GGCX), which catalyzes the post-transcriptional carboxylation of vitamin K-dependent proteins
MK-4 and MK-4 solutions of MK-4, MKH-DMG, or MKH-SUC in ethanol were irradiated with artificial sunlight chromenol, were determined by LC-MS/MS
Summary
Menahydroquinone-4 (MKH), the fully reduced and active form of MK-4, is a cofactor for γ-glutamyl carboxylase (GGCX), which catalyzes the post-transcriptional carboxylation of vitamin K-dependent proteins. MKH is produced by the enzymatic conversion of vitamin K1 and K3 in the body [1]. MKH is readily oxidized to MK-4, MK-4 is available for clinical use. Because vitamin K is highly unstable in light, it should be strictly protected from light exposure during manufacturing, preparation, storage, and treatment [10,11,12]. Vitamin K is phototoxic against cultured epidermis upon ultraviolet A (UVA) irradiation (dose 6 J/cm2 ) [13].
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