PMID- 15690152
OWN - NLM
STAT- MEDLINE
DCOM- 20051017
LR  - 20131121
IS  - 0340-5761 (Print)
IS  - 0340-5761 (Linking)
VI  - 79
IP  - 6
DP  - 2005 Jun
TI  - Metabolites of benzene are potent inhibitors of gap-junction intercellular 
      communication.
PG  - 303-11
AB  - Chronic exposure to benzene has been shown to lead to bone marrow depression and 
      the development of leukemia. The mechanism underlying the carcinogenicity of 
      benzene is unknown, although a number of genetic changes including chromosomal 
      aberrations have been associated with benzene toxicity. Metabolism of benzene is 
      required for the induced toxicological effects. We have investigated the effect 
      of trans,trans-muconaldehyde (MUC), hydroquinone (HQ), and four MUC metabolites 
      on gap-junction intercellular communication (GJIC). Inhibition of GJIC has been 
      considered a possible predictor of tumor promoters and non-genotoxic carcinogens, 
      and shown to result in perturbation of hematopoiesis. MUC was found to be a 
      strong inhibitor of GJIC (EC50=12 micromol L(-1)) in rat liver epithelial cells 
      IAR20, with potency similar to that of chlordane (EC50=7 micromol L(-1)). HQ 
      inhibited GJIC with an EC50 of 25 micromolmol L(-1), and the metabolite OH/CHO 
      with an EC50 of 58 micromol L(-1). The other MUC metabolites tested, CHO/COOH and 
      OH/COOH were weak inhibitors of GJIC whereas COOH/COOH had no effect. Benzene 
      itself had no effect on GJIC when tested in concentrations up to 20 micromol 
      L(-1). The relative potency observed for the metabolites on GJIC is similar to 
      their hematotoxic effects. The effect of MUC on GJIC was observed to take place 
      concordant with a dramatic loss of connexin 43 (Cx43) from the cells as 
      visualized by Western blotting. Substances with the ability to inhibit 
      Cx43-dependent GJIC have previously been observed to interfere with normal 
      hematopoietic development. The ability of benzene metabolites to interfere with 
      gap-junction functionality, and especially the dramatic loss of Cx43 induced by 
      MUC, should therefore be considered as a possible mechanism for benzene-induced 
      hematotoxicity and development of leukemia.
FAU - Rivedal, Edgar
AU  - Rivedal E
AD  - Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310, 
      Oslo, Norway. edgarr@labmed.uio.no
FAU - Witz, Gisela
AU  - Witz G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050203
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Connexin 43)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - J64922108F (Benzene)
SB  - IM
MH  - Animals
MH  - Benzene/metabolism/*toxicity
MH  - Blotting, Western
MH  - Cell Communication/*drug effects
MH  - Cell Line
MH  - Connexin 43/metabolism
MH  - Epithelial Cells/cytology/*drug effects
MH  - Gap Junctions/*drug effects
MH  - Liver/cytology
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Rats
EDAT- 2005/02/04 09:00
MHDA- 2005/10/18 09:00
CRDT- 2005/02/04 09:00
PHST- 2004/07/14 00:00 [received]
PHST- 2004/11/10 00:00 [accepted]
PHST- 2005/02/04 09:00 [pubmed]
PHST- 2005/10/18 09:00 [medline]
PHST- 2005/02/04 09:00 [entrez]
AID - 10.1007/s00204-004-0638-0 [doi]
PST - ppublish
SO  - Arch Toxicol. 2005 Jun;79(6):303-11. doi: 10.1007/s00204-004-0638-0. Epub 2005 
      Feb 3.