DT-diaphorase activity and the cytotoxicity of quinones in C3H/10T1/2 mouse embryo cells.
A permanent mouse fibroblast cell line derived from C3H mouse embryos, C3H/10T1/2 C18, was used to study the cytotoxicity of some model quinones under conditions in which DT-diaphorase (EC 1.6.99.2) activity was induced or inhibited. Sudan III [1-[[4-(phenylazo)phenyl]azo]-2-naphthalenol] and 3-methylcholanthrene (MCA), but not butylated hydroxyanisole (BHA), induced DT-diaphorase in a concentration-dependent manner. Induction of DT-diaphorase activity was dependent upon new RNA and protein synthesis, as shown by experiments employing actinomycin D and cycloheximide respectively. Induction of DT-diaphorase by Sudan III or MCA was associated with protection against the cytotoxicity of quinones as measured by a colony survival assay. When control and induced cells were also exposed to dicoumarol, a specific and potent inhibitor of DT-diaphorase, the cytotoxicity of the quinones in both control and induced cells was enhanced markedly. The results support the hypothesis that DT-diaphorase competes with one-electron quinone-reducing enzymes (such as cytochrome P-450 reductase) which generate auto-oxidizable semiquinones and forms more stable hydroquinones as an initial step in the detoxification of quinones in 10T1/2 cells.
Atallah
A S
AS
Institute for Toxicology, University of Southern California, Los Angeles 90033.
Landolph
J R
JR
Ernster
L
L
Hochstein
P
P
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D001728:Dicumarol / Q000494:pharmacology; D004790:Enzyme Induction; D005347:Fibroblasts / Q000187:drug effects; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases / Q000032:analysis* / Q000096:biosynthesis; D011809:Quinones / Q000494:pharmacology*
D011809:Quinones; D002083:Butylated Hydroxyanisole; D008748:Methylcholanthrene; D001728:Dicumarol; D001189:Aryl Hydrocarbon Hydroxylases; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases