Androst-4-ene-3,17-dione

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: published data

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Validation of an in vitro model for assessment of androstenedione hepatotoxicity using the rat liver cell line clone-9

Author:

Sahu SC et.al.

Year:

2008

Bibliographic source:

J. of Applied Toxicol. 28, 703-709

Reference 2

Reference Type:

publication

Title:

Effects of oral androstenedione on phospholipid fatty acids, ATP, caspase-3, prostaglandin E2 and C-reactive protein in serum and livers of pregnant and non-pregnant female rats

Author:

Wiesenfeld PW et.al.

Year:

2006

Bibliographic source:

Food and Chemical Toxicology 44, 579¿587

Reference 3

Reference Type:

publication

Title:

Effects of oral androstenedione on steroid metabolism in liver of pregnant and non-pregnant female rats

Author:

Flynn TJ et.al.

Year:

2005

Bibliographic source:

Food and Chemical Toxicology 43, 537¿542

Reference 4

Reference Type:

publication

Title:

Hepatotoxicity of androstenedione in pregnant rats

Author:

Sahu SC et.al.

Year:

2005

Bibliographic source:

Food and Chemical Toxicol. 43, 341-344

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Androst-4-ene-3,17-dione

EC Number:

200-554-5

EC Name:

Androst-4-ene-3,17-dione

Cas Number:

63-05-8

Molecular formula:

C19H26O2

IUPAC Name:

androst-4-ene-3,17-dione

Results and discussion

Any other information on results incl. tables

Effects of androstendione on liver studied.

Applicant's summary and conclusion

Executive summary:

In several publications, hepatotoxicity of Androstendione in vitro and in vivo was evaluated.

 

In an in vitro study, cultures of Clone-9 cells (non-transformed epithelial cell line that was originally

isolated from normal liver of a 4-week old Sprague-Dawley rat) were treated with androstenedione for 24 h at concentrations of 0-100 µg/ml. After the treatment period, the cells and the culture supernatants were assayed for markers of cytotoxicity which included: release of liver enzymes, cell viability, cellular double-stranded DNA content, oxidative stress, steatosis, cellular ATP content, caspase-3 activity, the mitochondrial permeability transition and induction of cytochrome P450 activity.

Significant concentration-dependent differences from control were observed in some endpoints (especially cell death and oxidative stress markers) at medium concentrations of 10 μg/ml and above. However, poor concordance between the hepatotoxicity of androstenedione in vitro in clone-9 cells and the hepatotoxicity of androstenedione in rats in vivo was observed, suggesting that the clone-9 cells are not a good model for predicting the hepatotoxicity of naturally occurring steroids (Sahu, 2008).

 

Mature female rats were gavaged with 0, 5, 30 or 60 mg/kg/day androstenedione beginning two weeks prior to mating and continuing through gestation day 19. Non-pregnant female rats were gavaged over the same time frame with 0 or 60 mg/kg/day androstenedione. Livers were removed from dams on gestation day 20 and from non-pregnant rats after five weeks_ treatment. Liver microsomes were incubated with 200 µM testosterone, and the reaction products were isolated and analyzed by HPLC. In pregnant rats, formation of 6a-, 15b-, 7a-, 16b-, and 2b-hydroxytestosterone was increased significantly vs. control at the highest dose level only. Formation of 6b-hydroxytestosterone increased significantly at both the 30 and 60 mg/kg/day dose levels. In non-pregnant rats, 60 mg/kg/day androstenedione significantly increased formation of 15b-, 6b-, 6b-, and 2b-hydroxytestosterone.

The data suggest that high oral doses of androstenedione can induce some female rat liver cytochromes P450 that metabolize steroid hormones and that the response to androstenedione does not differ between pregnant and non-pregnant female rats (Flynn, 2005).

 

Mature female rats were gavaged with 0, 5, 30 or 60 mg/kg/day androstenedione beginning two weeks prior to mating and continuing through gestation day 19. Non-pregnant female rats were gavaged over the same time frame with 0 or 60 mg/kg/day androstenedione. Serum was collected and livers were removed from dams on gestation day 20 and from non-pregnant rats after 5 weeks of treatment. Androstenedione had no effect on serum total cholesterol, triglycerides or HDL-cholesterol, but significantly decreased C-reactive protein in pregnant rats and prostaglandin E2 in serum of both pregnant and non-pregnant rats. There were treatment related decreases in liver ATP and, to a lesser degree, caspase-3 and no change in alkaline phosphatase of pregnant female rats. Androstenedione decreased docosahexaenoic acid in both serum and liver phospholipids of pregnant female rats. In conclusion, oral androstenedione did not result in overt hepatotoxicity in pregnant female rats, but produced modest changes in lipid metabolism and may impair regeneration of injured hepatic cells or tissue (Wiesenfeld, 2006).