Potential to induce lamellar bodies and acute cytotoxicity of 6'-alkyl analogues of spectinomycin in primary cultures of rat hepatocytes.
A study was undertaken to investigate the potential of 6'-alkyl analogues of spectinomycin (SPE) to induce cytotoxicity and the formation of lamellar bodies in rat hepatocytes in culture. The cultured hepatocytes were treated with SPE, 6'-propylspectinomycin (trospectomycin sulphate; TRO), 6'-pentylspectinomycin (PES) or 6'-ocytlspectinomycin (OCS) in increasing concentrations up to 2.5 mm in the tissue-culture medium for 24 hr. Assay of lactate dehydrogenase (LDH) release into the medium was used to assess cytotoxicity, and the formation of lamellar bodies was assessed by transmission electron microscopy (TEM). Acid phosphatase cytochemistry was used in conjunction with TEM to determine the relationship of lamellar bodies to the lysosome. Neither SPE nor TRO produced significant cytotoxicity at the concentrations tested. Cytotoxicity was observed with PES at all concentrations >/=0.5 mm, and with OCS at all concentrations >/=0.1 mm. The number of lamellar bodies per cell section was correlated with the length of the 6'-alkyl side chain, and the capacity of the compounds to induce lamellar bodies was ranked in the order OCS > PES > TRO. Lamellar bodies were not observed above control levels in SPE-treated hepatocytes. Lamellar bodies were observed to stain positive for acid phosphatase activity, indicating that they were lysosomal. We conclude that the length of the 6'-alkyl side chain of spectinomycin analogues is correlated with acute cytotoxicity and the induction of lamellar bodies.
Ulrich
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RG
Investigative Toxicology Research, 7228-209-0, The Upjohn Company, Kalamazoo, MI 49001, USA.
Cramer
C T
CT