Gap junction intercellular communication and benzene toxicity.
Aberrant regulation of gap junction intercellular communication (GJIC) has been linked to several human diseases, including cancer and abnormal hematopoietic development. Benzene exposure has been shown to cause hematotoxicity and leukemia, but the underlying mechanisms involved remain unclear. We have observed that several metabolites of benzene have the ability to block gap junction intercellular communication. The ring-opened trans,trans-muconaldehyde (MUC) was found to be the most potent inhibitor of gap junction channels. MUC was found to induce cross-linking of the gap junction protein connexin43, which seemed to be responsible for the induced inhibition of GJIC. Glutaraldehyde, which has a similar molecular structure as MUC, was found to possess similar effects on gap junctions as MUC, while the mono-aldehyde formaldehyde shows lower potency, both as a connexin cross-linker, and as an inhibitor of GJIC. Both glutaraldehyde and formaldehyde have previously been associated with induction of leukemia and disturbance of hematopoiesis. Taken together, the data support a possible link between the effect of MUC on gap junctions, and the toxic effects of benzene.
Rivedal
Edgar
E
Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital and Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway. edgarr@rr-research.no
Witz
Gisela
G
Leithe
Edward
E
D000447:Aldehydes / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D001554:Benzene / Q000009:adverse effects* / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects*; D008099:Liver / Q000166:cytology; D051381:Rats
D000447:Aldehydes; D018031:Connexin 43; C034476:muconaldehyde; D001554:Benzene