Differential expression of the tetracycline-controlled transactivator-driven human CYP1B1 gene in double-transgenic mice is due to androgens: application for detecting androgens and antiandrogens.
Differential expression of the tetracycline-controlled transactivator (tTA)-driven human cytochrome p450 (CYP) 1B1 gene was found in the livers of male mice, at high levels in neonates, but at low levels in adults. The goals of this study were to determine whether the differential expression of the tTA-driven human CYP1B1 (hCYP1B1) gene in neonates and adults was testosterone dependent and whether flutamide, a representative potent antiandrogen, led to the induction of hCYP1B1. This was tested by treating castrated transgenic mice with testosterone propionate and musk extracts. It was concluded that: (i). the levels of expression of both tTA and hCYP1B1 gradually declined, with clear changes being apparent between 2 and 4 weeks of age, (ii). castration of adult males resulted in the increased expressions of both tTA and hCYP1B1 to levels similar to those found in adult females, (iii). treatment of castrated male and adult female mice with testosterone propionate and musk extracts led to the restoration of the levels of expression of hCYP1B1 in the adult males, and (iv). treatment of adult males with flutamide caused an increase in the levels of expression of hCYP1B1 in the adult females, as indicated by the antiandrogenic activity. Thus, the differential expression of the tTA-driven hCYP1B1 gene in the transgenic mice was caused by androgen, and it is possible that castrated male and adult female mice expressing the tTA-controlled hCYP1B1 could be used as the basis for a strategy for the detection of androgens and antiandrogens.
Hwang
Dae Y
DY
Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul 122-704, Republic of Korea.
Cho
Jung S
JS
Chae
Kab R
KR
Kang
Tae S
TS
Hwang
Jin H
JH
Lim
Chae H
CH
Lee
Su H
SH
Lim
Hwa J
HJ
Min
Sae H
SH
Sheen
Yhun Y
YY
Jang
In S
IS
Kim
Yong K
YK
D000375:Aging; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000819:agonists / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D008822:Mice, Transgenic; D009919:Orchiectomy; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D013739:Testosterone / Q000494:pharmacology
D000726:Androgen Antagonists; D000728:Androgens; D005229:Fatty Acids, Monounsaturated; C008563:musk; D013739:Testosterone; D005485:Flutamide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1