The cytotoxicity of the "K-region"
epoxides as well as several other reactive metabolites or chemical derivatives of
polycyclic hydrocarbons was compared in normally-repairing human diploid skin fibroblasts and in fibroblasts from a classical
xeroderma pigmentosum (XP) patient (XP2BE) whose cells have been shown to carry out excision repair of damage induced in
DNA by ultraviolet (UV) radiation at a rate approx. 20% that of normal cells. Each compound tested exhibited a 2- to 3-fold greater cytotoxicity in this XP strain than in the normal strain. To determine whether this difference in survival reflected a difference in the capacity of the strains to repair DNA damage caused by such
hydrocarbon derivatives, we compared the cytotoxic effect of several "K-region"
epoxides in two additional XP strains, each with a different capacity for repair of UV damage. The ratio of the slopes of the survival curves for each of the XP strains to that of the normal strain, following exposure to each
epoxide, was very similar to that which we had previously determined for their respective UV curves, suggesting that human cells repair damage induced in
DNA by exposure to
hydrocarbon derivatives with the same system used for UV-induced lesions. To determine whether the deficiency in rate of excision repair in this classical XP strain (XP2BE) causes such cells to be abnormally susceptible to mutations induced by "K-region"
epoxides of
polycyclic hydrocarbons, we compared them with normal cells for the frequency of induced mutations to
8-azaguanine resistance. The XP cells were two to three times more susceptible to mutations induced by the "K-region"
epoxide of
benzo(a)pyrene (BP), 7,12-dimethyl-benz(a)anthracene (DMBA), and
dibenz(a,h)anthracene (DBA). Evidence also was obtained that cells from an XP variant patient are abnormally susceptible to mutations induced by
hydrocarbon epoxides and, as is the case following exposure to UV, are abnormally slow in converting low molecular weight
DNA, synthesized from a template following exposure to
hydrocarbon epoxides, into large-size
DNA.