title: Activities of xenobiotic metabolizing enzymes in rat placenta and liver in vitro.
abstract: In order to assess whether the placental metabolism of xenobiotic compounds should be taken into consideration for physiologically-based toxicokinetic (PBTK) modelling, the activities of seven phase I and phase II enzymes have been quantified in the 18-day placenta of untreated Wistar rats. To determine their relative contribution, these activities were compared to those of untreated adult male rat liver, using commonly accepted assays. The enzymes comprised cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), esterase, UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). In contrast to liver, no activities were measurable for 7-ethylresorufin-O-dealkylase (CYP1A), 7-pentylresorufin-O-dealkylase (CYP2B), 7-benzylresorufin-O-dealkylase (CYP2B, 2C and 3 A), UGT1, UGT2 and GST in placenta, indicating that the placental activity of these enzymes was well below their hepatic activity. Low activities in placenta were determined for FMO (4%), and esterase (8%), whereas the activity of placental ADH and ALDH accounted for 35% and 40% of the hepatic activities, respectively. In support of the negligible placental CYP activity, testosterone and six model azole fungicides, which were readily metabolized by rat hepatic microsomes, failed to exhibit any metabolic turnover with rat placental microsomes. Hence, with the possible exception of ADH and ALDH, the activities of xenobiotic-metabolizing enzymes in rat placenta are too low to warrant consideration in PBTK modelling.
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, GV/TB-/470, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Fabian
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE Wageningen, The Netherlands.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, GV/TB-/470, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Engel
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE Wageningen, The Netherlands.
authors.forename: Hequn
authors.initials: H
authors.lastname: Li
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, GV/TB-/470, 67056 Ludwigshafen am Rhein, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Landsiedel
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, GV/TB-/470, 67056 Ludwigshafen am Rhein, Germany; Division of Toxicology, Wageningen University, Tuinlaan 5, 6700 HE Wageningen, The Netherlands. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001393:Azoles / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010920:Placenta / Q000201:enzymology* / Q000378:metabolism; D011247:Pregnancy; D017208:Rats, Wistar; D013739:Testosterone / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D001393:Azoles; D015262:Xenobiotics; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D000444:Aldehyde Dehydrogenase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004950:Esterases
keywords: Rat liver; Rat placenta; Xenobiotic metabolizing enzymes