Research progress in biosynthesis of podophyllotoxin and its derivatives / 生物工程学报

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand. With the advantages of unconstrained resources and eco-friendly reaction conditions, biosynthesis method has become a trend in the production of PTOX and its derivatives. In this review, we summarize the research progress of PTOX biosynthesis in plants and expound the functions of the key enzymes as well as their subcellular location. The synthetic biology for production of PTOX intermediates in a tobacco chassis is also introduced. Finally, the heterologous expression and biotransformation of PTOX in microorganisms is summarized, which sets the foundation for the efficient microbial production of PTOX using cell factories.

Hepatoprotective and antioxidant activity of rhizome of Podophyllum hexandrum against carbon tetra chloride induced hepatotoxicity in rats / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To test possible antioxidant activity of n-hexane extract of Podophyllum hexandrum under in vitro and in vivo conditions.</p><p><b>METHODS</b>The in vitro antioxidant activity was evaluated by the ability of the extract to interact with the stable free radical DPPH, Superoxide (O2-), Hydroxyl (OH-), Hydrogen peroxide (H2O2) radicals, and reducing power ability of the extract was also evaluated. Under in vivo conditions the extract was evaluated for its hepatoprotective activity by measuring different biochemical parameters, such as serum alanine aminotransaminase, serum aspartate aminotransaminase and serum lactate dehydrogenase and antioxidant enzymes. Antioxidant status was estimated by determining the activities of antioxidative enzymes, glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD), and by determining the levels of reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS).</p><p><b>RESULTS</b>Hexane extract of P. hexandrum exhibited good radical scavenging capacity in neutralization of DPPH, O2-, OH-, and H2O2 radicals in a dose dependent manner. n-hexane extract of Podophyllum hexandrum at the doses of 20, 30, and 50 mg/kg-day produced hepatoprotective effect by decreasing the activity of serum marker enzymes, while it significantly increased the levels of glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), super oxide dismutase (SOD), and glutathione-S-transferase (GST) in a dose dependant manner. The effect of n-hexane extract was comparable to that of standard antioxidant vitamin E.</p><p><b>CONCLUSION</b>The extract of Podophyllum hexandrum possess free radical scavenging activity under in vitro conditions and could protect the liver tissue against CCl(4) induced oxidative stress probably by increasing antioxidant defense activities.</p>

Iron chelation and related properties of Podophyllum hexandrum, a possible role in radioprotection.

Aqueous extract of Podophyllum species has been reported to render significant protection against radiation induced mortality, cytogenetic damage and cell death. In view of this, present study was undertaken to investigate its antioxidant properties. Chelation, oxidation and reduction of Fe2+ and Fe3+ were measured using chelating agents 2-2' bipiridyl and potassium thiocyanate respectively. Podophyllum extract, in a dose dependent manner, chelated Fe2+ more efficiently than Fe3+ and also modulated Fe2+/Fe3+ ratio. Homogenate of mouse liver was used to measure TBARS for estimating lipid peroxidation. Podophyllum extract also inhibited lipid peroxidation in a dose dependent manner and maximum inhibition (92%) was achieved at 1000 micrograms/ml concentration. These results demonstrates that Podophyllum exhibits antioxidant properties as seen through chelation and modulation of redox state of iron ions and these may primarily contribute towards its radioprotective manifestation.

Antitumour and radioprotective action of Podophyllum hexandrum.

A significant antitumour effect of P. hexandrum, a herb thriving at Himalayas (2500-4000 m), was observed in strain 'A' mice carrying solid tumours developed by transplanting Ehrlich ascites tumour (EAT). Subtoxic well tolerated sequential doses of aqueous extract of P. hexandrum (a daily dose of 34.5 mg/kg b.w. for 15 days) enhanced tumour doubling time (TDT) from 1.94 +/- 0.26 days to 19.1 +/- 2.5 days. However, no synergism was revealed between radiation and P. hexandrum, though both independently manifested antitumour effects. In normal mice, pre-irradiation administration of extract of P. hexandrum protected mice in a dose dependent manner (optimal dose being 34.5 mg/kg body.wt. rendering 72% survival for 30 days) against whole body lethal irradiation of 10 Gy. Radioprotective properties of P. hexandrum were found to be comparable to synthetic radioprotectors like diltiazem etc.

A Case of Podophyllum Toxicity with Peripheral Polyneuropathy

A case is reported ofsystemic toxicity by topically applied podophyllin. The patient was a 18-year-old girl who was treated at private gynecological clinic with 25% podophyllin resin for multiple vulval condyloma acuminata. Her apparent podophyllin toxicity begun 4 hours after topical application, presenting gastrointestinal symptoms such as nausea, vomiting, diarrhea and abdominal distension, followed by tingling sensation on hands and feet with motor weakness predominantly of distal limbs. She had never experienced disturbance of consciousness or other CNS symptoms. The symptoms of severe peripheral neuropathy had been improved by 72 days followup when she had mild impairement of vibration and position sense and mild dorsiflexion weakness of the feet.