PMID- 6722987
OWN - NLM
STAT- MEDLINE
DCOM- 19840713
LR  - 20190511
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 5
IP  - 6
DP  - 1984 Jun
TI  - The genotoxicity of aromatic amines in primary hepatocytes isolated from C57BL/6 
      and DBA/2 mice.
PG  - 797-804
AB  - The capacity of the chemical carcinogen 2-acetylaminofluorene (AAF) and its 
      derivates to cause DNA damage in primary mouse hepatocytes from aryl-hydrocarbon 
      responsive C57BL/6 and non-responsive DBA/2 mice was studied using the alkaline 
      elution technique. Low levels of DNA damage were observed after exposure of 
      hepatocytes to either AAF or 2-aminofluorene (AF) (50-100 microM). Quantitation 
      of metabolites produced from AAF in hepatocytes from untreated C57BL/6 and DBA/2 
      mice using h.p.l.c. showed a similar metabolic profile with respect to C- and 
      N-hydroxylations. After in vivo pretreatment with the potent monooxygenase 
      inducer TCDD (50 micrograms/kg), N-hydroxylation in the C57BL/6- and 
      DBA/2-derived hepatocytes increased 25- and 5-fold, respectively. However, the 
      C-hydroxylation pathways were still responsible for approximately 90% of the 
      metabolism in cells from both strains. This may explain why only a slight 
      increase in the DNA damage was observed in C57BL/6 mouse hepatocytes after 
      incubation with AF or AAF and no increase in DNA damage was seen in the DBA/2 
      hepatocytes isolated from TCDD treated animals. Both 
      N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and N-acetoxy-2-acetylaminofluorene 
      (N- OAc -AAF) caused clear dose-dependent increases in DNA strand breaks (5-100 
      microM), suggesting that N-hydroxylation was the rate limiting step in the 
      activation process of AAF leading to the DNA damage. Treatment of hepatocytes 
      with paraoxon, an inhibitor of microsomal deacetylase activity, prior to exposure 
      to either N-OH-AAF or N- OAc -AAF completely inhibited the damage caused by 
      N-OH-AAF, while the damage caused by N- OAc -AAF was only partially inhibited. 
      This suggests that these compounds are causing genotoxic effects after 
      deacetylation. In accordance with this, N-hydroxy-2-aminofluorene (N-OH-AF), the 
      deacetylated metabolite of N-OH-AAF, was an effective genotoxic agent, causing 
      DNA strand breaks at low doses. Depletion of cellular glutathione by pretreatment 
      with diethyl maleate, increased the sensitivity of the cells to the damage 
      induced by N-OH-AF. These data indicate that glutathione may play an important 
      role in the detoxification of N-OH-AF in mouse hepatocytes.
FAU - Moller, M E
AU  - Moller ME
FAU - Glowinski, I B
AU  - Glowinski IB
FAU - Thorgeirsson, S S
AU  - Thorgeirsson SS
LA  - eng
PT  - Journal Article
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Carcinogens)
RN  - 0 (Fluorenes)
RN  - 3A69OS195N (2-aminofluorene)
RN  - 53-95-2 (Hydroxyacetylaminofluorene)
RN  - 6098-44-8 (Acetoxyacetylaminofluorene)
RN  - 9007-49-2 (DNA)
RN  - 9M98QLJ2DL (2-Acetylaminofluorene)
SB  - IM
MH  - 2-Acetylaminofluorene/metabolism/*toxicity
MH  - Acetoxyacetylaminofluorene/toxicity
MH  - Animals
MH  - Biotransformation
MH  - Carcinogens/*toxicity
MH  - DNA/metabolism
MH  - Fluorenes/*toxicity
MH  - Hydroxyacetylaminofluorene/toxicity
MH  - Kinetics
MH  - Liver/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred DBA
MH  - Structure-Activity Relationship
EDAT- 1984/06/01 00:00
MHDA- 1984/06/01 00:01
CRDT- 1984/06/01 00:00
PHST- 1984/06/01 00:00 [pubmed]
PHST- 1984/06/01 00:01 [medline]
PHST- 1984/06/01 00:00 [entrez]
AID - 10.1093/carcin/5.6.797 [doi]
PST - ppublish
SO  - Carcinogenesis. 1984 Jun;5(6):797-804. doi: 10.1093/carcin/5.6.797.