Effect of peripubertal androgen treatment on hepatic cytochrome P450 expression in adult female rats

• Main Author: Anderson, Mellissa Dawn
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/6401

The goal of the current study was to investigate the pubertal period as a time when androgen imprinting of hepatic CYP enzymes can occur. Female Sprague-Dawley rats were ovariectomized, at 25 days of age, and injected subcutaneously with androgens during the pubertal period, on days 35-49. Plasma testosterone levels were measured following the treatment. Rats were killed at 90 days of age and microsomes were prepared. Daily s.c. injections of testosterone enanthate at 5 umol/kg were able to increase adult testosterone 2a- and 16a- hydroxylase activities and CYP2C11 protein levels to 20% of control male levels. This enzyme is normally expressed in adult male rats only. Protein levels of CYP3A, a male-dominant enzyme, were increased 50%, although testosterone 6p-hydroxylase activity was not significantly increased. The increase in CYP3A was not attributed to CYP3A1 or CYP3A2. Neither CYP2A1 nor its marker activity, testosterone 7a-hydroxylase, was affected by pubertal testosterone enanthate injections. These results were compatible with the hypothesis that adult expression of certain CYP enzymes can be regulated by pubertal exposure to androgens. Injections of unesterified testosterone at 2.5 umol/kg twice daily had the same effect as a single dose of unesterified testosterone at 5 umol/kg/day in increasing expression of CYP2C11 and CYP3A and decreasing expression of CYP2A1. These results indicated that increases in dosing frequency of pubertal androgen to twice daily at 2.5 umol/kg did not affect adult CYP expression. Unesterified testosterone did not appear to be as effective as testosterone enanthate at elevating expression of CYP2C11 and CYP3A. This indicated a possible pharmacokinetic component, which was further supported by the difference in half-lives measured for the two androgens used. Smaller elevations in CYP2C11 and CYP3A expression were observed at 129 and 169 days of age than at 90 days of age. These results indicated that the effect of pubertal testosterone enanthate treatment was not permanent. The results of this study did not support the hypothesis of pubertal imprinting of hepatic CYP enzymes. It is likely that pharmacokinetic differences between testosterone and testosterone enanthate resulted in the varied response to the androgen formulations.