Benoxacor

Benoxacor (CGA 154281) is a herbicide safener and xenobiotic metabolism regulator. Benoxacor protects maize from the toxicity of metolachlor mainly by inducing detoxifying enzymes such as Glutathione S-transferase. Benoxacor also activates FXR, PXR and ERRα, and inhibits aromatase (aromatase). However, Benoxacor exhibits potential subacute oral toxicity and a high risk of hepatotoxicity in animal models. Benoxacor induces reactive oxygen species accumulation, interferes with embryonic heart development, and causes increased liver and kidney weights as well as alterations in gut microbiota in mice. Benoxacor can be used in studies related to hepatic steatosis, infertility, breast cancer and developmental toxicity^[1][2][3].
In Vitro:Benoxacor (5 μM; 0-30 min) is metabolized by liver microsomes from male C57BL/6 mice in a time-dependent and enantioselective manner. Cytochrome P450 enzymes primarily metabolize the E2-benoxacor enantiomer, while microsomal carboxylesterases mainly metabolize the E1-benoxacor enantiomer. The intrinsic clearance of microsomal CYP-mediated elimination is 1.05 mL/min/mg protein, with a normalized clearance of 40.22 mL/min/g liver, whereas the intrinsic clearance of microsomal CES-mediated elimination is 0.54 mL/min/mg protein, with a normalized clearance of 20.77 mL/min/g liver^[1].
Benoxacor (5 μM; 0-30 min) is metabolized in a time-dependent and enantioselective manner by glutathione S-transferase in the liver cytosol of male C57BL/6 mice, with an intrinsic clearance rate of 1.46 mL/min/mg protein and a normalized clearance rate of 132.52 mL/min/g liver for GST-mediated elimination^[1].
Benoxacor (10 μM; 0.25-48 h) is rapidly taken up by suspension-cultured cells of maize (cultivar: Black Mexican Sweet, same below), and the uptake amount increases continuously within 48 h after treatment with 10 μM^[3].
Treatment of maize suspension-cultured cells with Benoxacor (10 μM; 0-48 h) doubles the activity of GST-M, a change detectable as early as 4 h post-treatment and peaking at 24 h^[3].
Benoxacor (10 μM; 24 h) increases the activities of three distinct GSTs (a, c, d) isolated via anion exchange chromatography from treated maize suspension-cultured cells^[3].
Isolation of GST fractions (b, c, d) from maize suspension-cultured cells treated with Benoxacor (10 μM; 24 h) reveals GST polypeptides (26,000-27,000 M_r) that cross-react with maize GST I and GST I/III antisera, a pattern consistent with that observed in benzofenap-treated maize seedlings^[3].
Treatment of maize suspension-cultured cells with Benoxacor (10 μM; 24 h) increases GST-M activity by 3-fold, and this effect is partially blocked by pre-treatment with Cycloheximide (HY-12320) (10/100 μM; 2 h), indicating that this induction activity requires de novo protein synthesis^[3].
Treatment of maize suspension-cultured cells with Benoxacor (10 μM; 24 h) increases GST-M activity by 3-fold, and this enhancing effect is significantly blocked by pretreatment with Cordycepin (HY-N0262) (10/100 μM; 2 h), indicating that this inductive activity requires de novo RNA synthesis^[3]. In Vivo:Subacute oral exposure of male C57BL/6J mice to Benoxacor (0.5-50 mg/kg b.w.; oral gavage; daily; for 3 consecutive days). Exposure to 50 mg/kg causes a significant dose-dependent increase in body weight-corrected liver and testicular weights, and induces mild, post-correction statistically insignificant changes in hepatic gene expression, metabolomics, and intestinal bacterial genus abundance, but exerts no effect on hepatic antioxidant enzyme activity^[1].
Benoxacor (0.5-2.0 mg/L; waterborne exposure; continuous exposure; 5.5 to 72 hpf) induces concentration-dependent developmental toxicity, cardiac morphological and functional abnormalities, oxidative stress, as well as apoptosis and dysregulated expression of cardiac development-related genes in zebrafish embryos, with the most severe effects observed at the 2.0 mg/L dose^[2].