title: Close link between protoporphyrin IX accumulation and developmental toxicity induced by N-phenylimide herbicides in rats.
abstract: BACKGROUND
  S-53482, 7-fluoro-6-[(3,4,5,6-tetrahydro)phthalimido]-4-(2-propynyl)-1,4-benzoxazin-3(2H)-one (flumioxazin), is an N-phenylimide herbicide and developmentally toxic to rats, but not to rabbits. The day of greatest sensitivity to S-53482 is gestational day (GD) 12 in rats. There is a compound-specific difference in developmental toxicity among structurally similar compounds including S-23121 (N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide; teratogenic) and S-23031 (pentyl 2-chloro-4-fluoro-5-(3,4,5,6-tetrahydrophthalimido)phenoxyacetate (flumiclorac pentyl); nonteratogenic). The herbicidal action is due to photodynamic action of accumulating protoporphyrin IX (PPIX), resulting from the inhibition of protoporphyrinogen oxidase (PPO), an enzyme in porphyrin biosynthesis. Species difference in PPIX accumulation in embryos corresponded to those of the developmental toxicity. Our objective in this study was to further investigate a link between PPIX accumulation resulting from PPO inhibition and developmental toxicity. This article is part of a series of studies to be published serially.
  
  
  METHODS
  To investigate compound-specific differences, each compound was orally administered to rats on GD 12. To define peak period of PPIX accumulation, single oral treatments of S-53482 were given to rats or rabbits at 19:30 on GD 10 through GD 15. PPIX was extracted from embryos 14 hr after treatment.
  
  
  RESULTS
  Remarkable PPIX accumulation was observed when treated with S-53482 or S-23121, but not with S-23031. The greatest accumulation of PPIX was observed when treated with S-53482 at 19:30 on GD 11 or GD 12. No PPIX accumulation was found on any GDs in rabbits.
  
  
  CONCLUSIONS
  The developmentally toxic compounds caused PPIX accumulation in embryos. The peak period of PPIX accumulation corresponded to that of developmental effects. This correlation suggests a close link between PPO inhibition and developmental abnormality.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Konohana-ku, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawamura
authors.forename: Terushige
authors.initials: T
authors.lastname: Kato
authors.forename: Alan G
authors.initials: AG
authors.lastname: Fantel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines / Q000737:chemistry / Q000633:toxicity; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D006540:Herbicides / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D010797:Phthalimides / Q000737:chemistry / Q000633:toxicity; D050768:Protoporphyrinogen Oxidase / Q000037:antagonists & inhibitors*; D011524:Protoporphyrins / Q000378:metabolism* / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D064793:Teratogenesis / Q000187:drug effects
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D048588:Benzoxazines; D006540:Herbicides; D010797:Phthalimides; D011524:Protoporphyrins; C083440:S 23121; C028025:protoporphyrin IX; D050768:Protoporphyrinogen Oxidase; C106487:flumioxazin
keywords: N-phenylimide herbicide; compound-specific difference; developmental toxicity; peak period; porphyrin accumulation; rabbits; rats; teratogenicity