title: Oxymatrine inhibits hepatitis B infection with an advantage of overcoming drug-resistance.
abstract: Oxymatrine (OMTR) is an anti-hepatitis drug used in China. Its mechanism of action is unknown. Recently, we found that OMTR inhibits hepatitis B virus (HBV) via down-regulating the expression of heat-stress cognate 70 (Hsc70), a host protein required for HBV DNA replication. Goal of this study was to assess the effect of OMTR on clinical HBV drug-resistance. OMTR monotherapy (oral, 12 months) reduced blood HBV DNA by 96% and HBeAg by 70% in the chronic hepatitis B (CHB) patients resistant to lamivudine (n = 17), equal to its efficacy in the naïve CHB cohort (n = 20). Liver biopsy study showed that OMTR treatment caused a decrease of Hcs70 mRNA in liver cells, parallel with a reduction of intracellular HBV DNA. Combination of lamivudine with OMTR (n = 15) (oral, 12 months) showed an enhanced anti-HBV effect as compared to lamivudine monotherapy (n = 25). The incidence of drug resistance against lamivudine in the combination group was significantly lower than that in the lamivudine group (1/15 vs 7/25; p<0.01). The results were further confirmed in vitro. Treatment of HBV(+) HepH2215 cells with sub-optimal dose of OMTR for 8 months suppressed HBV replication without inducing drug resistance, whereas lamivudine monotherapy caused drug-resistant mutation in 3 months. Combination of OMTR with lamivudine prevented HBV from developing drug resistance.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Xue
authors.forename: Zhen-Xian
authors.initials: ZX
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Yan-Xing
authors.initials: YX
authors.lastname: Han
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Shan
authors.initials: S
authors.lastname: Cen
authors.forename: Hong-Shan
authors.initials: HS
authors.lastname: Chen
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Li
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000470:Alkaloids / Q000008:administration & dosage* / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001706:Biopsy; D002681:China; D004279:DNA, Viral / Q000097:blood; D015536:Down-Regulation; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling; D050883:HSC70 Heat-Shock Proteins / Q000096:biosynthesis; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011807:Quinolizines / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D019562:Viral Load; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D004279:DNA, Viral; D050883:HSC70 Heat-Shock Proteins; D006513:Hepatitis B e Antigens; D019259:Lamivudine; D011807:Quinolizines; C494371:HSPA8 protein, human; C037573:oxymatrine; D000093842:Matrines