Bioactivation and toxicity in vitro of HCFC-123 and HCFC-141b: role of cytochrome P450.
The bioactivation and cytotoxicity in vitro of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) and 1,1-dichloro-1-fluoroethane (HCFC-141b), two replacements for some ozone-depleting chlorofluorocarbons (CFC), were investigated in rat liver microsomes and isolated rat hepatocytes. Both compounds were activated by cytochrome P450 to reactive metabolites, as indicated by: (i) the depletion of exogenous and cellular glutathione, (ii) the increased LDH release from hepatocytes, (iii) the loss of microsomal P450 content and activities, and (iv) the formation of free radical species observed in the presence of the two compounds. Moreover, the formation of two stable metabolites and an increased production of conjugated dienes, a marker of lipid peroxidation, were observed for both HCFC-123 and HCFC-141b. The biotransformation of both compounds by pyridine- and phenobarbital-induced rat liver microsomes and the inhibition of LDH release by 4-methylpyrazole and troleandomycin indicate that P450 2E1, 2B and, possibly, also 3A are the isoforms involved in the bioactivation and toxicity of HCFC-123 and HCFC-141b in the rat.
Zanovello
A
A
Institute of Occupational Medicine, University of Padua, Via Facciolati, 71, 35128 Padua, Italy.
Ferrara
R
R
Tolando
R
R
Bortolato
S
S
White
I N
IN
Manno
M
M
D000818:Animals; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000378:metabolism* / Q000633:toxicity*; D064227:Chlorofluorocarbons, Ethane; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D011725:Pyridines; C067411:2,2-dichloro-1,1,1-trifluoroethane; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; C023666:pyridine; C068320:1,1-dichloro-1-fluoroethane; D010634:Phenobarbital