Dose-and time-dependent cytotoxicity of HCFC-123 and HCFC-141b on isolated rat hepatocytes under aerobic and hypoxic conditions

Manno, Maurizio; Zanovello, Alberta; Ferrara, Roberta; Tolando, Roberto

doi:10.1016/s0378-4274(98)80651-6

Cited by 2 publications

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“…The toxic eå ects of the compound were studied by measuring (1) the levels of conjugated dienes, in anaerobic liver microsomal incubations from pyridine-treated rats and (2) the release of cellular LDH or the depletion of total cellular glutathione, in isolated rat hepatocytes in suspension. Preliminary summary reports of parts of the present study have already been published (Manno et al 1998.…”

Section: Introductionmentioning

confidence: 98%

Bioactivation to free radicals and cytotoxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b)

et al. 2001

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1. The in vitro bioactivation by rat liver microsomes and the cytotoxicity in rat hepatocytes of 1,1-dichloro-1-fluoroethane (HCFC-141b), a replacement for some ozone depleting chlorofluorocarbons (CFC), have been investigated. 2. Anaerobic incubations of liver microsomes from pyridine-induced rats with HCFC-141b in the presence of the spin-trapping agent N-t-butyl-alpha-phenylnitrone (PBN) resulted in the formation of a typical ESR radical signal. 3. In the presence of HCFC-141b, a dose-dependent formation of conjugated dienes was observed that was partially inhibited by PBN, glutathione (GSH) and vitamin C. Moreover, HCFC-141b increased the release of lactate dehydrogenase (LDH) and the depletion of cellular glutathione in isolated rat hepatocytes under both normoxic and hypoxic conditions. 4. HCFC-141b-dependent cytotoxicity was completely prevented by PBN under both conditions and it was partially prevented under normoxic conditions by the broad-spectrum P450 inhibitor metyrapone, the P4502E1 specific inhibitor 4-methylpyrazole and the P4503A-specific inhibitor troleandomycin. Interestingly, HCFC-141b-dependent glutathione depletion was not prevented by PBN, metyrapone, 4-methylpyrazole or troleandomycin, whereas two glutathione depletors, 2,6-dimethyl-2,5-heptadien-4-one (phorone) and diethylmaleate, partially prevented LDH release. 5. The present results indicate that HCFC-141b is reductively metabolized in vitro to free radical intermediates by P450, in particular by the CYP2E1 and, to a lower extent, CYP3A isoforms, leading to peroxidative membrane damage and glutathione-independent cytotoxicity.

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Section: Introductionmentioning

confidence: 98%