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Bioreduction of 4-nitroquinoline 1-oxide in dysplastic nevus syndrome fibroblasts
R Mirzayans1, M Sabour, M C Paterson
1Molecular Genetics and Carcinogenesis Laboratory, Cross Cancer Institute, Edmonton, Alberta, Canada.
Abstract:
Fibroblast strains 3012T and 3072T, derived from normal skin explants of two patients affected with familial dysplastic nevus syndrome (DNS), an hereditary variant of cutaneous malignant melanoma, have been reported to be abnormally sensitive to the cytotoxic and mutagenic effects of the procarcinogen 4-nitroquinoline 1-oxide (4NQO). In this communication we demonstrate that on exposure to a particular concentration of 4NQO, these same two DNS strains sustain an amount of DNA damage which is equal to (3012T) or only approximately 1.3 times greater than (3072T) that displayed by 8 control fibroblast strains established from clinically normal volunteers. Moreover, cell sonicates of 3072T display approximately 1.3-fold enhanced capacity to catalyze the reduction of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide, whereas sonicates of 3012T cells carry out this reaction at a normal rate. Accordingly, our results argue against the postulate that the 4NQO hypersensitivity exhibited by these DNS strains is merely due to an elevated capacity for bioreduction of the inert parent compound to a DNA-reactive derivative.
Insights
Fibroblast strains from familial dysplastic nevus syndrome (DNS) patients show hypersensitivity to 4-nitroquinoline 1-oxide (4NQO). This sensitivity is not solely due to increased bioreduction of 4NQO to its active form.
Area of Science:
- Genetics
- Dermatology
- Carcinogenesis
Background:
- Familial dysplastic nevus syndrome (DNS) is an inherited condition increasing melanoma risk.
- Certain DNS fibroblast strains exhibit heightened sensitivity to 4-nitroquinoline 1-oxide (4NQO), a procarcinogen.
Purpose of the Study:
- To investigate the mechanism behind 4NQO hypersensitivity in DNS fibroblast strains.
- To determine if enhanced bioreduction of 4NQO contributes to its cytotoxic and mutagenic effects in DNS.
Main Methods:
- Cultured fibroblast strains from DNS patients (3012T, 3072T) and healthy volunteers were exposed to 4NQO.
- DNA damage levels were quantified in exposed cells.
- The enzymatic capacity of cell sonicates to reduce 4NQO was measured.
Main Results:
- DNS strains 3012T and 3072T sustained DNA damage levels comparable to or only slightly higher than control strains upon 4NQO exposure.
- Sonicates of 3072T cells showed a 1.3-fold enhanced capacity to reduce 4NQO to 4-hydroxyaminoquinoline 1-oxide.
- Sonicates of 3012T cells exhibited normal 4NQO reduction rates.
Conclusions:
- The hypersensitivity of these DNS fibroblast strains to 4NQO is not primarily caused by an elevated ability to convert 4NQO into its proximate carcinogen.
- Alternative mechanisms likely underlie the observed 4NQO sensitivity in familial dysplastic nevus syndrome.