PMID- 12102540
OWN - NLM
STAT- MEDLINE
DCOM- 20030207
LR  - 20170214
IS  - 0960-3271 (Print)
IS  - 0960-3271 (Linking)
VI  - 21
IP  - 3
DP  - 2002 Mar
TI  - Maternal and developmental toxicity in mice by aminophenylnorharman, formed from 
      norharman and aniline.
PG  - 147-51
AB  - 9-(4'-Aminophenyl)-9H-pyrido [3,4-b] indole (aminophenylnorharman, APNH) is a 
      novel mutagenic heterocyclic amine, produced by the reaction of norharman with 
      aniline in the presence of S9 mix. In the present study, the maternal and 
      developmental toxicity of APNH were investigated in ICR mice administered oral 
      doses of 0, 0.625, 1.25, 2.5 or 5 mg/kg/day on gestational days (GD) 6 through 15 
      or 0, 5, 10, or 20 mg/kg on GD 12. Maternal and foetal parameters were evaluated 
      on day 18 of gestation. Foetuses of dams treated on GD 6-15 were examined for 
      external and skeletal malformations and variations, and foetuses of dams treated 
      on GD 12 were inspected for cleft palate. Maternal death occurred when APNH was 
      administered at 5 mg/kg/day on GD 6-15. No significant decrease in body weight 
      gain during the administration period was observed at doses of 2.5 mg/kg/day or 
      less when applied on GD 6-15. Adverse changes in general condition of dams were 
      observed in the groups treated at doses of 2.5 mg/kg/day and above on GD 6-15, 
      whereas no adverse effects on dams were noted even when APNH was applied at a 
      fairly high dose on GD 12. Intracytoplasmic vacuolation in hepatocytes, necrosis 
      of proximal tubular epithelial cells and desquamation of necrotic epithelial 
      cells in the tubular lumen were observed in dams treated with APNH at 2.5 or 5 
      mg/kg/day on GD 6-15. Increased preimplantation loss was observed at 5 mg/kg/day 
      and post-implantation loss was observed at 2.5 mg/kg/day and above when applied 
      on GD 6-15, or at 20 mg/kg when applied on GD 12. Foetal body weight was 
      decreased by APNH in a dose-dependent manner. The frequency of external 
      malformations (cleft palate) was significantly increased in the group treated 
      with APNH at 2.5 mg/kg/ day on GD 6-15 compared to the controls. However, there 
      were no foetuses with cleft palate even when APNH was given at 20 mg/kg on GD 12. 
      No significant increases in skeletally malformed foetuses were found in any 
      APNH-treated group. The frequency of lumbar ribs was increased dose dependently. 
      This study demonstrated the developmental toxicity of a mutagenic compound, APNH, 
      in mice at maternally toxic doses, and that cleft palate observed in term 
      foetuses resulted from the adverse effect of APNH on the maternal environment 
      during organogenesis. More detailed studies are warranted to assess the possible 
      risks to pregnant women from exposure to APNH.
FAU - Naga, T
AU  - Naga T
AD  - Department of Life Science, Faculty of Science and Technology, Kinki University, 
      Osaka, Japan. nagaot@kb3.so-net.ne.jp
FAU - Yoshimura, S
AU  - Yoshimura S
FAU - Totsuka, Y
AU  - Totsuka Y
FAU - Wakabayashi, K
AU  - Wakabayashi K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Exp Toxicol
JT  - Human & experimental toxicology
JID - 9004560
RN  - 0 (Aniline Compounds)
RN  - 0 (Carbolines)
RN  - 0 (Indoles)
RN  - 0 (Mutagens)
RN  - 0 (Pyridines)
RN  - 4FHH5G48T7 (Harmine)
RN  - 94HMA1I78O (norharman)
RN  - NMC04J95OA (9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole)
RN  - SIR7XX2F1K (aniline)
SB  - IM
MH  - Aniline Compounds/chemistry
MH  - Animals
MH  - Carbolines
MH  - Cleft Palate/chemically induced
MH  - Female
MH  - Fetus/abnormalities/drug effects
MH  - Harmine/*analogs & derivatives/chemistry
MH  - Humans
MH  - Indoles/administration & dosage/chemical synthesis/*toxicity
MH  - Liver/drug effects/embryology/pathology
MH  - Male
MH  - Maternal Exposure/*adverse effects
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mutagens/administration & dosage/toxicity
MH  - Pregnancy
MH  - Pyridines/administration & dosage/chemical synthesis/*toxicity
EDAT- 2002/07/10 10:00
MHDA- 2003/02/08 04:00
CRDT- 2002/07/10 10:00
PHST- 2002/07/10 10:00 [pubmed]
PHST- 2003/02/08 04:00 [medline]
PHST- 2002/07/10 10:00 [entrez]
AID - 10.1191/0960327102ht227oa [doi]
PST - ppublish
SO  - Hum Exp Toxicol. 2002 Mar;21(3):147-51. doi: 10.1191/0960327102ht227oa.