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In vitro metabolism of chlorotriazines: characterization of simazine, atrazine, and propazine metabolism using liver microsomes from rats treated with various cytochrome P450 inducers



In vitro metabolism of chlorotriazines: characterization of simazine, atrazine, and propazine metabolism using liver microsomes from rats treated with various cytochrome P450 inducers



Toxicology and Applied Pharmacology 156(3): 195-205



The in vitro metabolism of chlorotriazines, simazine (SIZ), atrazine (ATZ), and propazine (PRZ) was studied using control, 3-methylcholanthrene-, phenobarbital-, pyridine-, dexamethasone-, and clofibrate-treated rat liver microsomes. The metabolites were determined by HPLC. The principal reactions by cytochrome P450 (P450) system were N-monodealkylation and isopropylhydroxylation in all rat liver microsomes. As a result, 2-chloro-4-ethylamino-6-amino-1,3,5-triazine (M1) (SIZ-M1 for SIZ and ATZ-M1 for ATZ) and 2-chloro-4-amino-6-isopropylamino-1,3, 5-triazine (M2) (ATZ-M2 for ATZ and PRZ-M2 for PRZ), 2-chloro-4-ethylamino-6-(1-hydroxyisopropylamino)-1,3,5-triazine (M3) (ATZ-M3 for ATZ), and 2-chloro-4-isopropylamino-6-(1-hydroxyisopropylamino)-1,3,5-triazi ne (M4) (PRZ-M4 for PRZ) were detected as the metabolites. N-bidealkylation and 2-hydroxylation were not found in this system. The formation rates of SIZ-M1, ATZ-M1, ATZ-M2, and PRZ-M2 were markedly induced by 3-methylcholanthrene, phenobarbital, and pyridine. On the other hand, the formation rates of ATZ-M3 and PRZ-M4 were significantly induced by phenobarbital, pyridine, and/or clofibrate, but not by 3-methylcholanthrene. The enzyme kinetics of chlorotriazine metabolism were examined by mean of Eadie-Hofstee analyses. Although there was no remarkable difference of Km for the products in chlorotriazine metabolism among the microsomes tested, the Vmax and Clint (Vmax/Km) for the products in chlorotriazine metabolism are affected by P450 inducers, except for dexamethasone. The formation rates of SIZ-M1, ATZ-M1, ATZ-M2, and PRZ-M2 were significantly correlated with 7-ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, 7-ethoxycoumarin O-deethylase, 4-nitrophenol 2-hydroxylase, and testosterone 7alpha-hydroxylase activities and CYP1A1/2 level, whereas the formation rates of ATZ-M3 and PRZ-M4 were significantly correlated with testosterone 16beta-hydroxylase, bufuralol 1'-hydroxylase, and 4-nitrophenol 2-hydroxylase activities and CYP2B1/2 level. These results suggest that the inducibility in metabolism of SIZ, ATZ, and PRZ is different between N-monodealkylation and isopropylhydroxylation and that the N-monodealkylation and isopropylhydroxylation are induced by CYP1A1/2, CYP2B1/2, and CYP2B1/2, respectively.

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Accession: 010814451

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PMID: 10222312

DOI: 10.1006/taap.1999.8648


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