Abstract
V79 cells, genetically engineered to express active cytochromes P450IIB1 and P450IA1, were used to study the cytotoxicity and mutagenicity of cyclophosphamide and ifosfamide. Cyclophosphamide, tested up to a concentration of 2 mM, was not cytotoxic in V79 nor in the P450IA1-expressing V79-derived cell line XEM2. Pronounced cytotoxicity was, however, observed in the P450IIB1-expressing V79-derived cell line SD1. Induction of gene mutations (acquisition of 6-thioguanine resistance) was observed in SD1 cells as well, but the effects were weak. Ifosfamide was inactive in V79 cells, but was cytotoxic in SD1 cells. Ifosfamide mustard, an active metabolite of ifosfamide, was equally cytotoxic and showed similar mutagenic effects in SD1 and parental V79 cells. The results indicate that cyclophosphamide and ifosfamide are metabolically activated by cytochrome P450IIB1. In contrast, cytochrome P450IA1 was not capable of activating cyclophosphamide. Thus, V79-derived cell lines defined for their expression of a specific form of cytochrome P-450 can be used as diagnostic tools to identify the cytochrome P-450 that is responsible for the metabolic activation of drugs.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Doehmer J., Dogra S., Friedberg T., Monier S., Adesnik M., Glatt H., Oesch F. Stable expression of rat cytochrome P-450IIB1 cDNA in Chinese hamster cells (V79) and metabolic activation of aflatoxin B1. Proc Natl Acad Sci U S A. 1988 Aug;85(16):5769–5773. doi: 10.1073/pnas.85.16.5769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glatt H., Oesch F. Activation of N-acetoxy- and N-hydroxy-2-acetylaminofluorene to mutagenic and cytotoxic metabolites by V79 Chinese hamster cells. Mutat Res. 1985 Apr;149(2):265–269. [PubMed] [Google Scholar]
- Hales B. F., Jain R. Characteristics of the activation of cyclophosphamide to a mutagen by rat liver. Biochem Pharmacol. 1980 Feb;29(2):256–259. doi: 10.1016/0006-2952(80)90338-x. [DOI] [PubMed] [Google Scholar]