Dataset Information

Pro-197-Ser Mutation and Cytochrome P450-Mediated Metabolism Conferring Resistance to Flucarbazone-Sodium in Bromus japonicus.

ABSTRACT: In crop fields, resistance to acetolactate synthase (ALS)-inhibiting herbicides found in many troublesome weed species, including Bromus japonicus Thunb, is a worldwide problem. In particular, the development of herbicide resistance in B. japonicus is a severe threat to wheat production in China. The purpose of this research was to investigate the physiological and molecular basis of B. japonicus resistance to flucarbazone-sodium. Dose-response analysis demonstrated that, compared with the susceptible B. japonicus (S) population, the resistant (R) population exhibited a 120-fold increase in flucarbazone-sodium resistance. Nucleotide sequence alignment of the ALS gene indicated that the Pro-197-Ser mutation in ALS was associated with resistance to flucarbazone-sodium in the R population. The results of a malathion pretreatment study showed that B. japonicus might also have remarkable cytochrome P450 monooxygenase (P450)-mediated metabolic resistance. This is the first report of a Pro-197-Ser mutation and P450-mediated metabolism conferring resistance to flucarbazone-sodium in B. japonicus.

SUBMITTER: Lan Y

PROVIDER: S-EPMC9269166 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Pro-197-Ser Mutation and Cytochrome P450-Mediated Metabolism Conferring Resistance to Flucarbazone-Sodium in Bromus japonicus.

Lan Yuning Y Zhou Xinxin X Lin Shenyuan S Cao Yi Y Wei Shouhui S Huang Hongjuan H Li Wenyu W Huang Zhaofeng Z

Plants (Basel, Switzerland) 20220621 13

In crop fields, resistance to acetolactate synthase (ALS)-inhibiting herbicides found in many troublesome weed species, including Bromus japonicus Thunb, is a worldwide problem. In particular, the development of herbicide resistance in B. japonicus is a severe threat to wheat production in China. The purpose of this research was to investigate the physiological and molecular basis of B. japonicus resistance to flucarbazone-sodium. Dose-response analysis demonstrated that, co ...[more]

PMID: 35807593

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Project description:AimLeflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo.MethodsThe metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg · kg(-1) · d(-1), ig) for 4 weeks, their blood samples were analyzed.ResultsA nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg(-1) · d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg(-1) · d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats.ConclusionHepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

Dataset Information

Pro-197-Ser Mutation and Cytochrome P450-Mediated Metabolism Conferring Resistance to Flucarbazone-Sodium in Bromus japonicus.

Publications

Pro-197-Ser Mutation and Cytochrome P450-Mediated Metabolism Conferring Resistance to Flucarbazone-Sodium in <i>Bromus japonicus</i>.

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