title: Effects of Sublethal Exposure to a Glyphosate-Based Herbicide Formulation on Metabolic Activities of Different Xenobiotic-Metabolizing Enzymes in Rats.
abstract: The activities of different xenobiotic-metabolizing enzymes in liver subcellular fractions from Wistar rats exposed to a glyphosate (GLP)-based herbicide (Roundup full II) were evaluated in this work. Exposure to the herbicide triggered protective mechanisms against oxidative stress (increased glutathione peroxidase activity and total glutathione levels). Liver microsomes from both male and female rats exposed to the herbicide had lower (45%-54%, P < 0.01) hepatic cytochrome P450 (CYP) levels compared to their respective control animals. In female rats, the hepatic 7-ethoxycoumarin O-deethylase (a general CYP-dependent enzyme activity) was 57% higher (P < 0.05) in herbicide-exposed compared to control animals. Conversely, this enzyme activity was 58% lower (P < 0.05) in male rats receiving the herbicide. Lower (P < 0.05) 7-ethoxyresorufin O-deethlyase (EROD, CYP1A1/2 dependent) and oleandomycin triacetate (TAO) N-demethylase (CYP3A dependent) enzyme activities were observed in liver microsomes from exposed male rats. Conversely, in females receiving the herbicide, EROD increased (123%-168%, P < 0.05), whereas TAO N-demethylase did not change. A higher (158%-179%, P < 0.01) benzyloxyresorufin O-debenzylase (a CYP2B-dependent enzyme activity) activity was only observed in herbicide-exposed female rats. In herbicide-exposed rats, the hepatic S-oxidation of methimazole (flavin monooxygenase dependent) was 49% to 62% lower (P < 0.001), whereas the carbonyl reduction of menadione (a cytosolic carbonyl reductase-dependent activity) was higher (P < 0.05). Exposure to the herbicide had no effects on enzymatic activities dependent on carboxylesterases, glutathione transferases, and uridinediphospho-glucuronosyltransferases. This research demonstrated certain biochemical modifications after exposure to a GLP-based herbicide. Such modifications may affect the metabolic fate of different endobiotic and xenobiotic substances. The pharmacotoxicological significance of these findings remains to be clarified.
authors.affiliation: Laboratorio de Biología y Ecotoxicología, Facultad de Ciencias Veterinarias, UNCPBA, Tandil, Argentina.|Laboratorio de Farmacología, Facultad de Ciencias Veterinarias (UNCPBA), Centro de Investigación Veterinaria Tandil (CIVETAN-CONICET), Tandil, Argentina.
authors.forename: Karen
authors.initials: K
authors.lastname: Larsen
authors.affiliation: Laboratorio de Biología y Ecotoxicología, Facultad de Ciencias Veterinarias, UNCPBA, Tandil, Argentina.
authors.forename: Roberto
authors.initials: R
authors.lastname: Najle
authors.affiliation: Laboratorio de Farmacología, Facultad de Ciencias Veterinarias (UNCPBA), Centro de Investigación Veterinaria Tandil (CIVETAN-CONICET), Tandil, Argentina.
authors.forename: Adrián
authors.initials: A
authors.lastname: Lifschitz
authors.affiliation: Laboratorio de Farmacología, Facultad de Ciencias Veterinarias (UNCPBA), Centro de Investigación Veterinaria Tandil (CIVETAN-CONICET), Tandil, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Maté
authors.affiliation: Laboratorio de Farmacología, Facultad de Ciencias Veterinarias (UNCPBA), Centro de Investigación Veterinaria Tandil (CIVETAN-CONICET), Tandil, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lanusse
authors.affiliation: Laboratorio de Farmacología, Facultad de Ciencias Veterinarias (UNCPBA), Centro de Investigación Veterinaria Tandil (CIVETAN-CONICET), Tandil, Argentina gvirkel@vet.unicen.edu.ar.
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Virkel
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000074409:Carbonyl Reductase (NADPH) / Q000737:chemistry / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000737:chemistry / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D062025:Organophosphate Poisoning / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D012727:Sex Characteristics; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism*; D000097797:Glyphosate
chemical_list: D015660:7-Alkoxycoumarin O-Dealkylase; D000074409:Carbonyl Reductase (NADPH); D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D005998:Glycine; D006540:Herbicides; D010105:Oxygenases; D014874:Water Pollutants, Chemical; D015262:Xenobiotics; D000097797:Glyphosate; C020066:dimethylaniline monooxygenase (N-oxide forming)
keywords: glyphosate; nontarget species; rats; xenobiotic-metabolizing enzymes