Photoreactivity of chloramphenicol in vitro and in vivo.
The negative side effects of chloramphenicol (CAP) mostly involve blood dyscrasias (e.g. irreversible non-dose-dependent aplastic anemia), allergic skin reactions and eye damage. To learn the cause of these side effects, most research focuses on metabolically formed nitroso- and hydroxylamino derivatives in the predisposed patient. In previous investigations it was demonstrated that photochemical decomposition of CAP in vitro by UV-A leads to formation of p-nitrobenzaldehyde (pNB), p-nitrobenzoic acid (pNBA) and p-nitrosobenzoic acid (pNOBA); the latter comprises up to 45 mol% of the starting amount of CAP. Incubation of these photoproducts in rat blood showed that pNB and pNOBA rapidly react and that PNBA is stable under these conditions. Reaction products from pNB (half-life 1.7 min) proved to be pNBA and p-nitrobenzyl alcohol (pNBOH) while pNOBA (half-life 3.7 min) was converted into p-aminobenzoic acid (pABA). Exposure of CAP in rat blood to UV-A yielded the same end products: pNBA, pABA and pNBOH. To estimate the amount of oxidative stress generated in vivo by these compounds, the ability to form methemoglobin (MetHb) in erythrocytes was tested; only pNOBA and p-hydroxylaminobenzoic acid (pHABA), a possible intermediate in the decomposition of pNOBA, proved to be reactive. Ultraviolet-A exposure of rats, after intraperitoneal injection of CAP, led to 3.6 times the basic level of MetHb. In addition, covalent binding of 3H-labeled CAP photoproducts to the skin of the back and to the ears was found, which was 9.1 and 3.2 times higher, respectively, than the dark values.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicinal Photochemistry, State University of Leiden, The Netherlands.
H
H
de Vries
P J
PJ
Hemelaar
A C
AC
Gevers
G M
GM
Beyersbergen van Henegouwen
D000818:Animals; D001547:Benzaldehydes / Q000097:blood; D001711:Biotransformation; D002701:Chloramphenicol / Q000097:blood / Q000493:pharmacokinetics / Q000528:radiation effects*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D009579:Nitrobenzoates / Q000097:blood; D009603:Nitroso Compounds / Q000097:blood; D010782:Photolysis; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014466:Ultraviolet Rays
D001547:Benzaldehydes; D009579:Nitrobenzoates; D009603:Nitroso Compounds; C029915:4-nitrobenzaldehyde; C090288:4-nitrosobenzoic acid; D002701:Chloramphenicol; C008629:4-nitrobenzoic acid