title: Silkworm as a model animal to evaluate drug candidate toxicity and metabolism.
abstract: To evaluate the feasibility of using the silkworm as a model animal for screening drug candidates, we examined whether the lethal dose of cytotoxic chemicals in silkworm, Bombyx mori, were consistent with those in mammals, and compared the metabolic pathways of these drugs between silkworms and mice. The lethal dose levels of cytotoxic chemicals in silkworms were consistent with those in mammals. We examined the fate of model drugs, 4-methyl umbelliferone, umbelliferone, and 7-ethoxycoumarine, in silkworm larvae. The half-life of 4-methyl umbelliferone in the silkworm larvae hemolymph was 7.0+/-0.1 min, similar to that in mouse blood. In silkworm larvae, 4-methyl umbelliferone was conjugated with glucose, whereas in mammals it is conjugated with glucuronate or sulfate. These results are consistent with a previous report that UDP-glucosyltransferase catalyzes the conjugation of 4-methyl umbelliferone. The glucose-conjugation reaction of 4-methyl umbelliferone was observed in microsomal fractions of fat bodies isolated from silkworms. Furthermore, most umbelliferone and 7-ethoxycoumarine injected into the hemolymph of silkworms was eliminated through the feces in the glucose-conjugated form. These findings suggest that chemicals are metabolized through a pathway common to both mammals and silkworms: reaction with cytochrome P450, conjugation with hydroxylated compounds, and excretion.
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamamoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tonoike
authors.forename: Kazuya
authors.initials: K
authors.lastname: Narushima
authors.forename: Ryo
authors.initials: R
authors.lastname: Horie
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sekimizu
mesh_terms: D000818:Animals; D001711:Biotransformation; D012831:Bombyx / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D003374:Coumarins / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005240:Feasibility Studies; D005243:Feces / Q000737:chemistry; D005965:Glucuronates / Q000378:metabolism; D006458:Hemolymph / Q000378:metabolism; D006923:Hymecromone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019476:Insect Proteins / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D023421:Models, Animal; D018675:Toxicity Tests / Q000379:methods*; D014468:Umbelliferones / Q000493:pharmacokinetics
chemical_list: D003374:Coumarins; D005965:Glucuronates; D019476:Insect Proteins; D014468:Umbelliferones; C017299:7-ethoxycoumarin; D006923:Hymecromone; C031477:7-hydroxycoumarin; D003577:Cytochrome P-450 Enzyme System