Induction of micronuclei and of enzyme-altered foci in the liver of female rats exposed to progesterone and three synthetic progestins.
Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg kg-1 3 days before partial hepatectomy and sacrificed for cell sampling 2 days later, the frequency of micronucleated hepatocytes was 3.5-fold higher than in controls with PG, 2.8-fold with DG, 2.2-fold with NE and 2.1-fold with AE, but the increase was statistically significant only for PG. In the liver foci assay, performed to evaluate the tumor initiating activity of p. o. dosing with 100 mg kg-1 once a week for 6 successive weeks, the values of the number and area of gamma-glutamyltranspeptidase-positive foci were, as compared to controls, 15.9- and 100-fold higher with NE, and 13.9- and 52-fold higher with AE, but only the increase of area produced by NE was statistically significant; PG and DG did not display in this test any activities. Considered together with previous findings, these results suggest that NE might be biotransformed in the liver into reactive species and thus behave as a weak genotoxic agent.
Martelli
A
A
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, I-16132, Genoa, Italy.
Mereto
E
E
Ghia
M
M
Orsi
P
P
Allavena
A
A
De Pascalis
C R
CR
Brambilla
G
G
D000500:Allylestrenol / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D017373:Cyproterone Acetate / Q000737:chemistry / Q000633:toxicity; D004394:Dydrogesterone / Q000737:chemistry; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009640:Norethindrone / Q000737:chemistry / Q000633:toxicity; D011374:Progesterone / Q000633:toxicity*; D045167:Progesterone Congeners / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase
D002273:Carcinogens; D009153:Mutagens; D045167:Progesterone Congeners; D011374:Progesterone; D017373:Cyproterone Acetate; D004394:Dydrogesterone; D005723:gamma-Glutamyltransferase; D000500:Allylestrenol; D009640:Norethindrone