Structure-toxicity relationship of cefoperazone and its impurities to developing zebrafish by transcriptome and Raman analysis.

Cefoperazone (CFP) is a potent antibacterial agent that is widely used for the treatment of bacterial infections. Previously, we found that both the C-7 and C-3 substituents of CFP are toxic functional groups, and two groups could affect gene expression in zebrafish embryos, thereby resulting in variable abnormal phenotypes. (6R, 7S)-cefoperazone (7S-CFP) is the 7-epimer of CFP and 1-methyl-1H-tetrazole-5-thiol (MTT) is the C-3 substituent of CFP. Both molecules are impurities isolated from CFP that can induce adverse effects. Transcriptome analysis was performed in the present study to identify differentially expressed genes (DEGs), coupled with Raman mapping of individual organ regions to detect changes in the biochemical composition of zebrafish embryos, which reflect the differences in distribution of the compounds. CFP, 7S-CFP, and MTT exposure altered the expression of 254, 368, and 1153 genes, respectively. Gene ontology analysis revealed that various processes related to development, growth, and morphology of tissues were significantly enriched with DEGs. We integrated seven co-DEGs with protein-protein interaction networks and identified various developmental processes that were regulated by the three compounds, including vasodilation, eye, brain, melanogenesis, and heart looping. Our findings suggested that Calca and Ptger4a may be potentially utilized as novel biomarkers for CFP, which causes bleeding. Raman analysis indicated that CFP, 7S-CFP, and MTT exhibited abnormal maps in tissues, which coincided with changes in their expression and morphological features. This study may provide bioinformatics and spectral information that may be used in further investigations on the relationship between structure and toxicity of drugs and impurities.

A study of the nephrotoxicity of three cephalosporins in rabbits using 1H NMR spectroscopy.

Male New Zealand White rabbits received a single intravenous injection of 125 mg/kg cephaloridine, 500 mg/kg cefoperazone or 1000 mg/kg cephalothin. Histological examination of kidneys at 48 h post-dose confirmed the presence of bilateral necrosis of the proximal convoluted tubules in the cephaloridine-treated animals. 1H-NMR urinalysis of cephaloridine-treated rabbits detected drug-related resonances, decreased hippurate and increased glucose at 0-24 h post-dose accompanied by elevated levels of lactate, glycine, citrate, glutamine/glutamate and alanine at 24-48 h post-dose. No histopathological changes were observed following administration of cefoperazone or cephalothin. 1H-NMR spectra of urine collected from these animals showed drug-related resonances and decreased hippurate levels at 0-24 h post-dose, and increased glucose levels at 24-48 h post-dose. Analysis of urine by conventional clinical-chemistry failed to reveal any statistically significant differences between the treatment groups. Under the conditions of this study, the nephrotoxic effects of cephaloridine and the minimal effects of cefoperazone and cephalothin could be clearly distinguished by 1H-NMR urinalysis but not by conventional urinalysis.

NMR study of whole rat bile: the biliary excretion of cefoperazone and benzyl chloride by an isolated perfused rat liver.

1H NMR spectroscopy at 400 MHz has been applied to the analysis of whole bile samples produced by the isolated perfused rat liver. Using relatively simple NMR experiments biliary excretory products of cefoperazone and benzyl chloride were identified as cefoperazone itself and a benzyl-glutathione conjugate, respectively. Our use of 13C isotopic labelling demonstrates how 1H/13C heteronuclear NMR techniques can be used to produce uncrowded and informative spectra from whole bile. From the use of a HMQC-COSY experiment the structure of a benzyl-glutathione conjugate contained in whole bile was confirmed.

Effect of the topical application of some newer antibiotics on the cerebral cortex.

Five currently used antibiotics--moxalactam, cefotaxime, cefoperazone, metronidazole, and piperacillin--and bacitracin were compared for epileptogenetic effect against penicillin G as a standard when applied directly to cat cerebral cortex. Piperacillin was half as epileptogenic as penicillin. Moxalactam, cefotaxime, and cefoperazone showed epileptogenicity one-fourth to one-eighth that of penicillin on a milligram per cubic centimetre basis. Neither metronidazole nor bacitracin produced any focal seizure activity at the highest concentrations tested. Some of the newer cephalosporin antibiotics may have a significant risk of inducing seizure activity if high concentrations come in direct contact with neocortical tissue.

Retinal toxicity of intravitreal cefoperazone.

Cefoperazone is a broad spectrum, third-generation cephalosporin with potential usefulness in treating endophthalmitis because of its in vitro activity against Gram-negative organisms. Retinal toxicity was evaluated via serial indirect ophthalmoscopy, electrophysiologic testing and histopathologic examination of 43 Dutch-belted rabbit eyes injected intravitreally with 2, 4, 8, 16 or 32 mg of cefoperazone in a volume of 0.1 cc each. They were compared with seven eyes injected with sterile saline. Results show electroretinographic and histological evidence of retinal toxicity at concentrations of 16 mg or greater, while a single intravitreal dose of 8 mg or less of cefoperazone produced no evidence of retinal toxicity.

A pharmacokinetic study of cefoperazone.

A pharmacokinetic study of cefoperazone on rats showed long half-life in serum and kidney. The most remarkable finding was that the drug was not detected in the fraction of mitochondria and lysosomes in all the experiment animals. The finding suggests the low nephrotoxic characteristics of cefoperazone.

Toxic effects of some antibiotics on rabbit kidney cells.

The cellular toxicity of some antibiotics (cephaloridine, cefazolin, cefoperazone and gentamicin) was studied in vitro using rabbit kidney cell cultures. In order to evaluate the importance of the different factors causing toxic effects, the authors studied the correlations between toxicity and antibiotic concentration and between toxicity and period of contact. The toxic effects were measured by LDH release and by neutral red uptake inhibition. In both tests, gentamicin clearly showed curvilinear dose-toxicity and time-toxicity correlation but the cephalosporins did not do so in either test. However the antibiotics tested all showed various degrees of toxicity, suggesting that their specific toxic activity on renal cells was greater than that of aspecific variables linked to pharmacokinetic behaviour.