Transmembrane distribution of kanamycin and chloramphenicol: insights into the cytotoxicity of antibacterial drugs

Abstract

Antibiotics are widely used and their abuse has caused ecological hazard. Recently, pollution from pharmaceuticals and personal care products (PPCPs) has aroused great concern among governments and researchers. In order to elucidate the correlations among molecular structure, transmembrane distribution and toxicological effects of different kinds of antibiotics, zebrafish (Danio rerio) embryos and larvae were exposed to two structurally different antibiotics, kanamycin (KAN) and chloramphenicol (CAP). The membrane distribution and toxicological effects of these antibiotics were investigated. The association of KAN with the embryos fitted a general Langmuir isotherm and was attributed to electrostatic attraction and hydrogen bond formation. The saturation number of KAN is 252 +/- 13 nmol per embryo and the adsorption constant (5.24 +/- 0.05) x 10(3) L mol(-1). The interaction of CAP with the embryos conformed to a general model of partitioning behavior with the partition coefficient being 14.20 +/- 0.94 microL per embryo, and was attributed to hydrophobic effects. More than 89% of the adsorbed KAN was located on the outer surface of the embryonic chorion, but over 80% of the adsorbed CAP entered the internal matrix. High antibiotic concentrations were lethal to most embryos, while low concentrations were teratogenic. KAN and CAP had different transmembrane distribution and their toxicities differed in character. KAN mainly accumulated on the outer membrane caused e.g. axial malformation (AM). In contrast, CAP readily went through the membrane into the cytoplasm and caused e.g. serious pericardial edema (PE), yolk sac edema (YSE) and hemagglutination (HE). The new method could be useful for evaluating the interactions of toxins with membranes and elucidating the mechanisms of cytotoxicity.

Teratological Effects of a Panel of Sixty Water-Soluble Toxicants on Zebrafish Development

“…14,38,77,79 Pericardial oedema induced by glycyrrhizin has also been reported in a human adult. 80 Other literatures are consistent with the compound-specific malformation reported here (Fig.…”

Transmembrane transports of acrylamide and bisphenol A and effects on development of zebrafish (Danio rerio)

“…The early life stage (ELS) test using zebrafish embryos has been widely used to investigate the acute and chronic toxicity of chemicals that cause significant environmental and human health risks [41][42][43]. Furthermore, as the zebrafish shares many morphological and physiological characteristics with mammals, toxicological results from studies of zebrafish embryo development can be used to evaluate developmental toxicity in higher vertebrates [44,45]. Therefore, zebrafish embryos are an ideal model for studying vertebrate developmental toxicity, and the ELS test has become an effective method for testing adult fish.…”

Developmental Toxicity of Diclofenac and Elucidation of Gene Regulation in zebrafish (Danio rerio)

“…The amount associated with the embryo decreased when NaCl exceeded 0.15 M. Increased ionic strength often favors hydrophobic interactions, thus facilitating the association of diclofenac with the embryo, while a higher concentration of electrolyte weakens embryo activity and thus affects the binding of diclofenac28. Higher temperatures favored the association of diclofenac with the embryo because an increase of the membrane flow rate accelerated metabolic activity28. However, more than 40°C could affect embryo activity adversely, so the amount of diclofenac associated was slightly reduced.…”

“…Results indicated that, like other hydrophobic drugs in transmembrane transport studies, e.g. chloramphenicol, most of the drug remained in the extracellular solution28. However, only half of the diclofenac associated the membrane was transported into the cytoplasm, compared to over 80% of the adsorbed chloramphenicol28.…”

“…chloramphenicol, most of the drug remained in the extracellular solution28. However, only half of the diclofenac associated the membrane was transported into the cytoplasm, compared to over 80% of the adsorbed chloramphenicol28. The different distribution behaviors of these drugs might be related to membrane lipid composition and the lipid-water partition coefficients.…”