Species, sex and inter-individual differences in DNA repair induced by nine sex steroids in primary cultures of rat and human hepatocytes.

Mutat Res. 2003 Apr 20;536(1-2):69-78.

Species, sex and inter-individual differences in DNA repair induced by nine sex
steroids in primary cultures of rat and human hepatocytes.

Martelli A, Mattioli F, Angiola M, Reimann R, Brambilla G.

Department of Internal Medicine, Division of Clinical Pharmacology and
Toxicology, University of Genoa, Viale Benedetto XV 2, I-16132, Genoa, Italy.

Sex steroids, due to the generally negative responses observed in routinely
employed standard genotoxicity assays, are considered epigenetic carcinogens.
Some doubts on this conviction are raised by the results of recent studies
providing evidence that cyproterone acetate and two structural analogues,
chlormadinone acetate and megestrol acetate, are genotoxic in female rats but
only for the liver, and in primary human hepatocytes from donors of both genders.
The experimental evidence suggests that the metabolic activation of these
molecules to reactive species and the consequent formation of DNA adducts occur
only in the intact hepatocyte. Since the possibility that other sex steroids
cause a liver-specific genotoxic effect cannot be ruled out a priori, we
investigated nine drugs of this family for their ability to induce DNA repair
synthesis in primary cultures of rat and human hepatocytes. Each steroid was
tested in cultures from at least two male and two female donors of each species.
Hepatocytes were exposed for 20h to sub-toxic concentrations ranging from 1 to 50
micro M, and DNA repair induction was measured by quantitative autoradiography.
In primary rat hepatocytes, induction of DNA repair indicative of a frankly
positive response was detected in cultures from: 2/2 males and 3/3 females with
drospirenone, 2/2 males and 1/2 females with ethinylestradiol, 1/2 males and 1/2
females with oxymetholone, 1/2 males with norethisterone, 1/4 females with
progesterone, and 1/4 males with methyltestosterone. Consistent negative
responses were obtained with testosterone and stanozolol. A few inconclusive
responses were observed in rat hepatocytes exposed to progesterone,
medroxyprogesterone, norethisterone, methyltestosterone and oxymetholone. In
contrast, under the same experimental conditions the nine sex steroids provided
frankly negative responses in the large majority of cultures of primary
hepatocytes from both male and female human donors; the only exceptions being the
inconclusive responses obtained in cultures from two of the donors exposed to
norethisterone and to ethinylestradiol, and from one of the donors exposed to
testosterone, methyltestosterone, and stanozolol. These results and previous
findings concerning cyproterone and its structural analogues suggest that sex
steroids differ for their ability to induce DNA repair, and that their
genotoxicity may be: (i) different in rat and human hepatocytes, (ii) dependent
on the sex of the donor, and (iii) affected by inter-individual variability.