Effects of synthetic androgens on liver function using the rabbit as a model.
The objective of this study was to determine whether the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0-13 with 17α-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7, and 14, were determined. As expected, T (10 mg/kg/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) increased BSP retention, and AST, ALT, GGT, and SDH levels, indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/d) increased BSP retention and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/d did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/d. For the androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the synthetic androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.
Hild
Sheri Ann
SA
BIOQUAL Inc, Division of Reproductive Endocrinology and Toxicology, Rockville, Maryland, USA. hildsa@mail.nih.gov
Attardi
Barbara J
BJ
Koduri
Sailaja
S
Till
Bruce A
BA
Reel
Jerry R
JR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008777:Methyltestosterone / Q000494:pharmacology; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D019055:No-Observed-Adverse-Effect Level; D011817:Rabbits; D013448:Sulfobromophthalein; D013739:Testosterone / Q000494:pharmacology; D045165:Testosterone Congeners / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000097:blood
C555235:11-methyl-19-nortestosterone-17-dodecylcarbonate; D045165:Testosterone Congeners; C555234:dimethandrolone-undecanoate; D013448:Sulfobromophthalein; D013739:Testosterone; C064709:trestolone; D009277:Nandrolone; D007064:L-Iditol 2-Dehydrogenase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008777:Methyltestosterone