Effects of synthetic androgens on liver function using the rabbit as a model

Abstract

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.

Figures

Figure 1

Serum levels of the liver enzymes, AST, ALT, GGT, and SDH in rabbits dosed orally with 10 mg/kg/day of T (A) or MT (B) for 14 days. Data points represent mean ± SE, n=3.

Figure 2

Serum levels of the liver enzymes, AST, ALT, GGT, and SDH, in rabbits dosed orally with 10, 3 or 1 mg/kg/day of DMAU for 14 days (Panels A, B, C, respectively). Data points represent mean ± SE, n=3.

Figure 3

Serum levels of DMA in rabbits dosed orally for 14 days with DMAU. The AUC0–14days for each dose level is presented and are expressed as ng/ml*day. Means with different letters are significantly different from one another (p<0.05). Data points and AUC values represent mean ± SE, n=3.

Figure 4

Serum levels of the liver enzymes, AST, ALT, GGT, and SDH, in rabbits dosed orally with 10, 3 or 1 mg/kg/day of MENT for 14 days (Panels A, B, C, respectively). Data points represent mean ± SE, n=3.

Figure 5

Serum BSP (A) and liver enzyme (B) levels in rabbits dosed orally with 25 mg/kg/day of the synthetic androgen 11β-MNTDC for 14 days. The AUC0–20min for BSP levels is presented in Panel A and are expressed as μg/ml*min. Data points and AUC values represent mean ± SE, n=3.

Figure 6

Serum levels of 11β-MNT in rabbits dosed orally for 14 days with 11β-MNTDC. The AUC0–14days for each dose level is presented and are expressed as ng/ml*min. Data points and AUC values represent mean ± SE, n=3.

Figure 7

BSP dye retention in rabbits dosed orally for 14 days with 10 mg/kg/day of T, MT, DMAU, MENT or 11β-MNTDC. %BSP retention was calculated as AUC0–20 min Day14/AUC0–20 min Day 0 × 100. Bars with different letters are significantly different (p<0.05) from one another; bars and brackets represent mean ± SE, n=3. Dashed line represents baseline which was defined as 100%.