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Amiodarone can cause pulmonary toxicity along with an increase in phospholipid in macrophages, lymphocytes, and other cell types. Phospholipid accumulates because amiodarone inhibits the lysosomal phospholipases A1 and A2. Since a wide array of cells are affected by amiodarone and because amiodarone might inhibit other phospholipases, we postulated that cellular functions might be affected. Therefore, the major focus of this study was to determine whether amiodarone inhibited cellular functions. We found that alveolar macrophages isolated from drug-fed rats were significantly less phagocytic, and that the rats had significantly depressed delayed-type hypersensitivity responses. Spleen cells isolated from the drug-fed rats also had severely depressed mitogen responses. Since the spleen cell proliferative response could be partially restored by stimulating the cells with ionomycin and phorbol myristate acetate, we postulated that amiodarone was inhibiting phospholipase C. To substantiate this hypothesis, we found that amiodarone could directly inhibit phospholipase C in vitro. We conclude that amiodarone affects both phagocytic responses and the development of cell-mediated immunity and that the lack of these normal responses could exacerbate amiodarone toxicity. One possible mechanism for decreased cellular functions may be the inhibition of phospholipase C. However, further studies are necessary to confirm this finding.

To investigate the hypotheses that amiodarone-induced pulmonary inflammation may be related to direct drug toxicity, groups of 10 or more Wistar rats were fed amiodarone by gavage at concentrations of 175, 300, 400, and 500 mg/kg/day, or vehicle alone. After 6 wk of drug feeding, the rats were examined for histologic and cellular evidence of pulmonary inflammation. In addition, the amounts of amiodarone, the major metabolite of amiodarone N-desethylamiodarone (N-des), and phospholipid in the lungs were determined. We found that rats fed 175 mg/kg of amiodarone were essentially no different from control animals. The 175 mg/kg group had normal lung histologies, no change in lavage cell counts or differential counts, and very little amiodarone, N-des, or phospholipid in the lungs. In contrast, the three high-dose groups had abnormal lung histologies along with increases in lavage cell counts and change in differential counts. There were also significant increases in the amounts of amiodarone, N-des, and phospholipid in the lung. We conclude that the development of amiodarone-induced pulmonary inflammation is dose dependent, and that there is a direct correlation between the amount of amiodarone, N-des, and phospholipid in the lung with the development of inflammation. It therefore appears that the drug is directly toxic to lung tissue.

SUMMARY: Lysine auxotrophs have been isolated from Pseudomonas aeruginosa 8602. Three of the mutants were deficient in diaminopimelate decarboxylase and accumulated meso- and ll-diaminopimelic acid (DAP) but otherwise were indistinguishable from the parent strain. The fourth mutant required lysine for optimal growth, grew slowly on meso- but not ll-DAP, and the DAP which accumulated in large amounts was solely the ll-isomer. This mutant was deficient in diaminopimelate epimerase. No significant differences were detected between its wall composition and that of the parent strain but it was particularly sensitive to carbenicillin.

Amber mutants of bacteriophage ${\rm T}_{4}{\rm D}$ were used to prepare phage head and tail components. The isolated heads and tails were purified and their response in aqueous suspension to ionizing radiation measured. The radiosensitivities were compared with that of whole bacteriophage. Both the heads and tails were inactivated exponentially. The Do (37% survival) of the tails was 1.6 krad compared with 1.2 krad for whole phage and 5.0 krad for heads. In nutrient broth the DNA containing heads were similar but slightly more sensitive to radiation than whole phage, while the protein tails were considerably more resistant. In dilute suspension however the tails were similar but slightly more resistant to radiation than whole phage but the heads were substantially more resistant than tails or whole phage. The major lethal target for phage irradiated in dilute aqueous solution is probably located in the tail.

Amber mutants of bacteriophage ${\rm T}_{4}{\rm D}$ were used to study the relative radiosensitivity of the head component and of the tail component of the phage under various experimental conditions. In the presence of radical scavenging agents the protein tails were considerably less sensitive to ionizing radiation than the intact, whole phage, whereas the DNA-containing heads were slightly more sensitive than whole bacteriophage. The Do (37% survival) of anoxic tails was 900 krad and 26 krad for heads. Addition of cysteamine reduced the radiosensitivity of phage heads and whole phage but had no effect on the tails. Likewise oxygen had a protective effect on the heads and whole phage but did not alter the radiosensitivity of the tails. Irradiation had no effect on the in vitro assembly method used for measuring the heads and tails.