IN VITRO METABOLISM OF ¹⁴C-PESTICIDAL CARBAMATES BY FETAL AND MATERNAL BRAIN, LIVER, AND PLACENTA OF THE RAT

¹ Department of Pharmacology, Loma Linda University School of Medicine

The phenyl N-methylcarbamates, Zectran and Mesurol, are anticholinesterase insecticides. The in vitro metabolism of these carbamates by fetal and material tissues of Sprague-Dawley rats was investigated. The major ether-extractable metabolite resulting from Zectran metabolism in fetal and maternal brain in vitro was the N-demethylated compound 4-methylamino-3,5-xylyl methylcarbamate (MA). Fetal brain and maternal brain converted 12.2% and 11.7%, respectively, of the ¹⁴C-Zectran added in vitro to MA. Fetal liver and placenta possessed no metabolic activity toward Zectran. Maternal liver had the highest metabolic activity of any of the tissues examined. N-Demethylation (15.8%) and N-methyl hydroxylation (13.6%) were the quantitatively important routes of metabolism identified. Sulfoxidation and hydroxylation to ether-soluble metabolites were the major routes of metabolism identified in studies with Mesurol. Both of these routes occurred in maternal liver (12.3% and 7.9%, respectively). Fetal liver possessed significant sulfoxidation activity (23.1%). The proportion of ¹⁴C-containing compounds that became water-soluble upon incubation with fetal liver was 36.0%, compared to 3.8% in controls, which contained boiled tissue. Placental tissue produced a small amount of the sulfoxide, 4-methylsulfinyl-3,5-xylyl methylcarbamate (3.2%). Fetal and maternal brain possessed no measurable metabolic activity toward Mesurol. These results may be of significance because it appears that toxic metabolites may be produced by fetal tissues subsequent to placental transfer; thus, MA and Mesurol-sulfoxide are more potent acetylcholinesterase inhibitors in vitro than their parent compounds.