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PHOTOREAaIVITY OF CHLORAMPHENICOL in vitro AND in vivo
Author(s) -
Vries Henk de,
Hemelaar Peter J.,
Gevers Alice C. M.,
Van Henegouwen Gerard M. J. Beyersbergen
Publication year - 1994
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.1994.tb05099.x
Subject(s) - chloramphenicol , in vitro , in vivo , chemistry , microbiology and biotechnology , biology , antibiotics , biochemistry
The negative side effects of chlorarnphenicol (CAP) mostly involve blood dyscrasias (e.g. irreversible nondose‐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 ( p NB), p‐nitrobenzoic acid ( p NBA) and p ‐nitrosobenzoic acid ( p NOBA); the latter comprises up to 45 mol% of the starting amount of CAP. Incubation of these photoproducts in rat blood showed that p NB and p NOBA rapidly react and that P NBA is stable under these conditions. Reaction products from p NB (half‐life 1.7 min) proved to be p NBA and p ‐nitrobenzyl alcohol ( p NBOH) while p NOBA (half‐life 3.7 min) was converted into p ‐aminobenzoic acid ( p ABA). Exposure of CAP in rat blood to UV‐A yielded the same end products: p NBA, P ABA and p NBOH. To estimate the amount of oxidative stress generated in vivo by these compounds, the ability to form methemoglobin (MetHb) in erythrocytes was tested; only p NOBA and p ‐hydroxylaminobenzoic acid ( p HABA), a possible intermediate in the decomposition of p NOBA, 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 3 H‐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. Toxicity toward bone marrow cells of all photoproducts was established in vitro. p ‐Nitrobenzaldehyde, p NOBA and p HABA were 20, 6 and 6 times more toxic than CAP, respectively. These results show that photodecomposition of CAP in vivo does occur. Its reactive photoproducts are able to cause damage that may lead to (systemic) side effects. The latter is supported by the fact that the nature of the reactive products, nitroso‐ and hydroxylamino derivatives, is the same as the expected metabolites.