Comparative evaluation of a 5-day Hershberger assay utilizing mature male rats and a pubertal male assay for detection of flutamide's antiandrogenic activity.
A 5-day Hershberger assay utilizing mature male rats and a pubertal male assay were evaluated for the ability to detect antiandrogenic compounds such as flutamide, an androgen receptor antagonist. Six days after the operation, implantation with two silicon capsules containing testosterone (T) (30 mg/capsule) in castrated rats provided the ventral prostate and seminal vesicle weights as well as serum T and luteinizing hormone (LH) levels equivalent to those of the controls (non-castrated, non-implanted rats). Castrated rats implanted with two T-capsules (6 rats/dose) were treated by gavage for 5 days with vehicle (0.5% carboxymethylcellulose) or flutamide (0.15, 0.6, 2.5, or 10 mg/kg/day). Flutamide produced significant decreases in weights of the seminal vesicles and the levator ani plus bulbocavernosus muscles (> or =0.6 mg/kg/day) and ventral prostate (> or =2.5 mg/kg/day), and an increase in serum LH levels (> or =2.5 mg/kg/day), but no changes in serum T levels. When age-matched intact male rats were treated with 10-mg/kg/day flutamide, a significant increase in serum T levels was observed concomitant with a tendency of increased LH. The organ weights were also decreased; however, the changes were less than those in the castrated, T-implanted rats. Immature intact male rats (10 rats/dose) were treated for 20 days with flutamide (0, 0.15, 0.6, 2.5, or 10 mg/kg/day). Flutamide produced significant decreases in weights of the seminal vesicles, ventral prostate, and levator ani plus bulbocavernosus muscles at 2.5 and 10 mg/kg/day. Serum LH levels, but not T levels, were increased at 10 mg/kg/day. Statistical significance of some of these changes was not observed in the 6 animals/dose examined. Our findings support that the Hershberger assay, in the current conditions, is the most sensitive among the assays examined and a useful short-term screening method for the detection of antiandrogenic compounds.
Yamada
T
T
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan. yamadat8@sc.sumitomo-chem.co.jp
Kunimatsu
T
T
Sako
H
H
Yabushita
S
S
Sukata
T
T
Okuno
Y
Y
Matsuo
M
M
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D005485:Flutamide / Q000633:toxicity*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010388:Pelvis; D010410:Penile Erection / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects / Q000473:pathology; D012680:Sensitivity and Specificity; D012741:Sexual Maturation / Q000187:drug effects*; D013739:Testosterone / Q000097:blood / Q000494:pharmacology; D018675:Toxicity Tests / Q000379:methods*
D000726:Androgen Antagonists; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone