Abstract
Studies were undertaken to examine the interaction of chloramphenicol and some of its analogs with DNA in an effort to elucidate the mechanism by which high levels of the drug cause inhibition of DNA synthesis. Chloramphenicol at concentrations of 1 mM and above was found to mediate the degradation of double-stranded DNA in the presence of copper and a reducing agent. Similarly, the l-threo steroisomer of chloramphenicol was equally potent at causing strand scissions in DNA. Nitroso-chloramphenicol, which inhibits DNA synthesis at much lower concentrations, also causes DNA damage at levels 100-fold lower than chloramphenicol. In contrast, thiamphenicol, which has a methyl-sulfonyl group in place of the nitro group at the para position, neither affects DNA synthesis nor causes DNA degradation under the conditions tested. The good correlation between the inhibition of DNA synthesis and the generation of strand-scissions by this series of analogs suggests that damage to DNA may be responsible for the inhibition of DNA synthesis seen with chloramphenicol, rather than an interaction of chloramphenicol with DNA polymerase. This proposal is further substantiated by studies with a DNA polymerase in a cell-free system. There was no inhibition of DNA synthesis when any of the analogs were added directly to the polymerase reaction mixture. However, a significant, time-dependent reduction in DNA synthesis was seen when the DNA template used for the polymerase assay was preincubated with chloramphenicol or nitroso-chloramphenicol prior to its use in the assay, again suggesting damage to DNA as the mechanism involved.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 926-932 |
| Number of pages | 7 |
| Journal | The Journal of laboratory and clinical medicine |
| Volume | 102 |
| Issue number | 6 |
| State | Published - 1983 |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
- Pathology and Forensic Medicine
Cite this
Chloramphenicol-mediated DNA damage and its possible role in the inhibitory effects of chloramphenicol on DNA synthesis. / Murray, Thomas R.; Downey, Kathleen M.; Yunis, Adel A.
In: The Journal of laboratory and clinical medicine, Vol. 102, No. 6, 1983, p. 926-932.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chloramphenicol-mediated DNA damage and its possible role in the inhibitory effects of chloramphenicol on DNA synthesis
AU - Murray, Thomas R.
AU - Downey, Kathleen M.
AU - Yunis, Adel A
PY - 1983
Y1 - 1983
N2 - Studies were undertaken to examine the interaction of chloramphenicol and some of its analogs with DNA in an effort to elucidate the mechanism by which high levels of the drug cause inhibition of DNA synthesis. Chloramphenicol at concentrations of 1 mM and above was found to mediate the degradation of double-stranded DNA in the presence of copper and a reducing agent. Similarly, the l-threo steroisomer of chloramphenicol was equally potent at causing strand scissions in DNA. Nitroso-chloramphenicol, which inhibits DNA synthesis at much lower concentrations, also causes DNA damage at levels 100-fold lower than chloramphenicol. In contrast, thiamphenicol, which has a methyl-sulfonyl group in place of the nitro group at the para position, neither affects DNA synthesis nor causes DNA degradation under the conditions tested. The good correlation between the inhibition of DNA synthesis and the generation of strand-scissions by this series of analogs suggests that damage to DNA may be responsible for the inhibition of DNA synthesis seen with chloramphenicol, rather than an interaction of chloramphenicol with DNA polymerase. This proposal is further substantiated by studies with a DNA polymerase in a cell-free system. There was no inhibition of DNA synthesis when any of the analogs were added directly to the polymerase reaction mixture. However, a significant, time-dependent reduction in DNA synthesis was seen when the DNA template used for the polymerase assay was preincubated with chloramphenicol or nitroso-chloramphenicol prior to its use in the assay, again suggesting damage to DNA as the mechanism involved.
AB - Studies were undertaken to examine the interaction of chloramphenicol and some of its analogs with DNA in an effort to elucidate the mechanism by which high levels of the drug cause inhibition of DNA synthesis. Chloramphenicol at concentrations of 1 mM and above was found to mediate the degradation of double-stranded DNA in the presence of copper and a reducing agent. Similarly, the l-threo steroisomer of chloramphenicol was equally potent at causing strand scissions in DNA. Nitroso-chloramphenicol, which inhibits DNA synthesis at much lower concentrations, also causes DNA damage at levels 100-fold lower than chloramphenicol. In contrast, thiamphenicol, which has a methyl-sulfonyl group in place of the nitro group at the para position, neither affects DNA synthesis nor causes DNA degradation under the conditions tested. The good correlation between the inhibition of DNA synthesis and the generation of strand-scissions by this series of analogs suggests that damage to DNA may be responsible for the inhibition of DNA synthesis seen with chloramphenicol, rather than an interaction of chloramphenicol with DNA polymerase. This proposal is further substantiated by studies with a DNA polymerase in a cell-free system. There was no inhibition of DNA synthesis when any of the analogs were added directly to the polymerase reaction mixture. However, a significant, time-dependent reduction in DNA synthesis was seen when the DNA template used for the polymerase assay was preincubated with chloramphenicol or nitroso-chloramphenicol prior to its use in the assay, again suggesting damage to DNA as the mechanism involved.
UR - http://www.scopus.com/inward/record.url?scp=0021045365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0021045365&partnerID=8YFLogxK
M3 - Article
C2 - 6644156
AN - SCOPUS:0021045365
VL - 102
SP - 926
EP - 932
JO - Translational Research
JF - Translational Research
SN - 1931-5244
IS - 6
ER -