PMID- 25475126
OWN - NLM
STAT- MEDLINE
DCOM- 20150824
LR  - 20181202
IS  - 1542-9741 (Electronic)
IS  - 1542-9733 (Linking)
VI  - 101
IP  - 6
DP  - 2014 Dec
TI  - Close link between protoporphyrin IX accumulation and developmental toxicity 
      induced by N-phenylimide herbicides in rats.
PG  - 429-37
LID - 10.1002/bdrb.21133 [doi]
AB  - 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.
CI  - (c) 2014 Wiley Periodicals, Inc.
FAU - Kawamura, Satoshi
AU  - Kawamura S
AD  - Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Konohana-ku, 
      Osaka, Japan.
FAU - Kato, Terushige
AU  - Kato T
FAU - Fantel, Alan G
AU  - Fantel AG
LA  - eng
PT  - Journal Article
DEP - 20141204
PL  - United States
TA  - Birth Defects Res B Dev Reprod Toxicol
JT  - Birth defects research. Part B, Developmental and reproductive toxicology
JID - 101155115
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abcg2 protein, rat)
RN  - 0 (Benzoxazines)
RN  - 0 (Herbicides)
RN  - 0 (Phthalimides)
RN  - 0 (Protoporphyrins)
RN  - 84478-52-4 (S 23121)
RN  - C2K325S808 (protoporphyrin IX)
RN  - EC 1.3.3.4 (Protoporphyrinogen Oxidase)
RN  - L0PX7OGI22 (flumioxazin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - Animals
MH  - Benzoxazines/chemistry/toxicity
MH  - Embryonic Development/*drug effects
MH  - Female
MH  - Herbicides/chemistry/*toxicity
MH  - Liver/metabolism
MH  - Phthalimides/chemistry/toxicity
MH  - Protoporphyrinogen Oxidase/*antagonists & inhibitors
MH  - Protoporphyrins/*metabolism/*pharmacokinetics
MH  - Rabbits
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Teratogenesis/drug effects
OTO - NOTNLM
OT  - N-phenylimide herbicide
OT  - compound-specific difference
OT  - developmental toxicity
OT  - peak period
OT  - porphyrin accumulation
OT  - rabbits
OT  - rats
OT  - teratogenicity
EDAT- 2014/12/06 06:00
MHDA- 2015/08/25 06:00
CRDT- 2014/12/06 06:00
PHST- 2014/09/24 00:00 [received]
PHST- 2014/11/06 00:00 [accepted]
PHST- 2014/12/06 06:00 [entrez]
PHST- 2014/12/06 06:00 [pubmed]
PHST- 2015/08/25 06:00 [medline]
AID - 10.1002/bdrb.21133 [doi]
PST - ppublish
SO  - Birth Defects Res B Dev Reprod Toxicol. 2014 Dec;101(6):429-37. doi: 
      10.1002/bdrb.21133. Epub 2014 Dec 4.