Induction of apoptosis in human lung fibroblasts and peripheral lymphocytes in vitro by Shosaiko-to derived phenolic metabolites.
Shosaiko-to is a Kampo medicine used for the treatment of chronic hepatitis in Japan. Lately, over 200 cases of interstitial pneumonia have been reported resulting from Shosaiko-to therapy, and the number of cases increased when patients were administrated interferon (IFN)-alpha at the same time. However, the mechanisms of this Shosaiko-to implicated interstitial pneumonia are not fully understood. In this study, we examined by flow cytometry analysis the in vitro effects of 7 phenolic compounds (lignans and flavonoids), which were detected from human urine after administration of Shosaiko-to, and IFN-alpha on inducing apoptosis in human lung fibroblasts and peripheral blood mononuclear cells (PBMCs). Among the 7 compounds, baicalein and medicarpin (10 microg/ml) showed significant apoptosis-inducing effects on human PBMCs. In human lung fibroblasts, medicarpin exhibited a significantly higher activity to induce apoptosis compared to the control, and the percentage of cells undergoing apoptosis showed time- and dose-dependent increases. Baicalein (0.1 and 1 microg/ml), liquiritigenin (10 microg/ml) and davidigenin (10 microg/ml) also showed significant effects after 96 h treatment. Whereas, baicalin, oroxylin A and wogonin did not show any effect on inducing apoptosis in PBMCs and fibroblasts. Baicalein and medicarpin significantly inhibited the growth and reduced the viability of lung fibroblasts. IFN-alpha had no apoptosis-inducing effect, and it did not show synergistic interaction with any of the compounds derived from Shosaiko-to on inducing apoptosis in both human lung fibroblasts and PBMCs. These results suggested that phenolic compounds found in human post-administrative urine of Shosaiko-to, especially baicalein and medicarpin, exhibited a direct effect on human lung fibroblasts and immune cells to induce apoptosis.
Liu
Zhen-Li
ZL
Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Tanaka
Sachiko
S
Horigome
Hiroshi
H
Hirano
Toshihiko
T
Oka
Kitaro
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D016898:Interferon-alpha; D010636:Phenols; C461320:shosaiko-to