The Regulation by Growth Hormone of Microsomal Testosterone 6β-Hydroxylase in Male Rat Livers1

Yamazoe, Yasushi; Shimada, M.; Murayama, Norie; Kawano, Sumie; Kato, Ryuichi

doi:10.1093/oxfordjournals.jbchem.a121790

Cited by 49 publications

(11 citation statements)

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“…The pre sent results, together with the results by Yamazoe et al (44) and Colby et al (43), support the view that a form (s) of cytochrome P-450 responsible for the 6,3-hydroxylation is regulated by gonadal hormones via the hy pophysis and leads to the occurrence of sex related differences of steroid metabolism in some species of animals, including rats and hamsters.…”

Section: Discussionsupporting

confidence: 74%

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Interspecies homology of cytochrome P-450: Inhibition by anti-P-450-Male antibodies of testosterone hydroxylases in liver microsomes from various animal species including man.

et al. 1989

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Abstract-P-450-male is one of the male-specific forms of cytochrome P-450 in liver microsomes of adult rats and functions as testosterone 2a and 1 6a-hydroxy lases. The purpose of this study was to examine whether forms of cytochrome P-450 cross-reactive with anti-P-450-male antibodies are present in liver micro somes of other animal species, such as male and female mice, rabbits, guinea pigs, hamsters, dogs and humans.The antibodies cross-reacted with a protein(s) in the liver microsomes of all animal species to show one or more bands on nitro cellulose paper by Western blot peroxidase-anti-peroxidase staining analysis. Qualitative as well as quantitative species differences were noted in the testosterone hydroxylases.The antibodies inhibited 2a-hydroxylase in male rats, 1 6a-hydroxy lase in male rats and male and female dogs, 7a-hydroxylase in female rats and male and female mice and hamsters, and 15a-hydroxylase in female mice and hamsters. No clear inhibition of 6i3-hydroxylase, which was present in all animal species, was observed.These results indicate that forms of cytochrome P-450 that are im munochemically related with P-450-male catalyze the hydroxylation of testosterone at varying positions depending on the animal species, with the exception of 6(3 hydroxylation, which may be catalyzed by a distinct form of cytochrome P-450.

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Section: Discussionsupporting

confidence: 74%

“…Recently, Yamazoe et al (44) reported that testosterone 6e9-hydroxylase in rats was regulated by pituitary hormones, but in a manner distinct from P-450-male.…”

Section: Discussionmentioning

confidence: 99%

Interspecies homology of cytochrome P-450: Inhibition by anti-P-450-Male antibodies of testosterone hydroxylases in liver microsomes from various animal species including man.

et al. 1989

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“…It is said that age-related changes in P450 are, in part, associated with the serum levels of hormones, such as testosterone and growth hormone (GH), which also change with age. CYP3A2 expression is regulated by GH [29] and disappears in old male rats [7], which is similar to our results on CYP3A in APA hamsters. Therefore, it is also likely in APA hamsters that some isozymes of P450 are regulated by GH and sex steroids, or other endocrine factors.…”

Section: Discussionsupporting

confidence: 92%

Localization and Age-Related Changes in Cytochrome P450 Expression in APA Hamster Livers.

Takatori

Akahori²,

Kawamura

et al. 2000

Exp. Anim.

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Abstract:To establish the baseline data, age-related changes and the regional expression of the hepatic P450 isozymes in Syrian hamsters of the APA strain at 3, 6, 12, 18 months old were examined by immunological techniques. Immunohistochemical analysis of liver serial sections revealed that the midzonal and perivenous regions (zones 2 and 3, respectively) were stained with the anti-rat CYP1A1/2, 2B1/2 and 2E1 antibodies. These three antibodies most intensely stained the hepatocytes around the central vein. An anti-rat CYP3A2 staining section had a staining pattern with equally intense reactions in zones 2 and 3. On the other hand, CYP2C6, 2C11 and 4A1 were distributed diffusely throughout the hepatic acinus. There was no age-related difference in the expression pattern of any of the P450 isozymes examined. Total P450 content had a peak at 6 months of age and decreased to 60% of that level thereafter. Western-blot analysis revealed that the peak expressions of the isozymes detected with anti-rat CYP1A1/2, 2C6, 2E1 and 3A2 antibodies were observed in 6-month-old hamsters and declined in older ones. The CYP2B and 2C11 content reached the maximum at the age of 6 months and maintained almost the same level thereafter. The CYP4A level did not change from 3 to 6 months, and then declined to about 40% of the younger level at 12 and 18 months of age. These results suggest that the hepatic P450 isozymes of APA hamsters have region-specific expressions and most isozymes have their peaks of expression at 6 months of age, which differs from the patterns for rat P450.

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“…This result was evident despite coadministration with either CsA or CsA vehicle. Similarly, a previous study has reported depression of 6␤-OHT levels after 7 days in intact male rats given GH in both intermittent pulses as well as in a continuous infusion (Yamazoe et al, 1986). Because the continuous presence of GH has been shown to decrease CYP3A2 activity in male rats and the long-term intermittent pulses used for this study resulted in a decrease in the activity of CYP3A1/2, this indicates that CYP3A1/2 may be responsive to an overall chronic increase in circulating GH levels.…”

Section: Discussionsupporting

confidence: 67%

Suppression of Hepatic CYP3A1/2 and CYP2C11 by Cyclosporine Is Not Mediated by Altering Growth Hormone Levels

Callahan

Brunner

2003

J Pharmacol Exp Ther

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Cyclosporine (CsA) suppresses drug metabolism by decreasing cytochrome P450 (P450) enzyme levels in rat liver. Growth hormone (GH) is known to pretranslationally regulate P450 expression. Thus, the suppression of P450 by CsA may involve GH as an intermediate. To address this question, we examined the effects of administering exogenous GH via twice daily subcutaneous injections and in conjunction with chronic subcutaneous CsA administration for 14 days on hepatic P450 expression. CsA alone decreased CYP3A1/2 and CYP2C11 significantly, in a manner similar to that previously found. When administered in the absence of CsA, GH also suppressed CYP3A1/2 and CYP2C11 protein levels as compared with GH vehicle. In the presence of CsA, GH did not cause further suppression of either CYP3A1/2 or CYP2C11 expression when compared with CsA treatment with GH vehicle. Testosterone in vitro catalytic assays confirmed that CsA and GH separately cause significant decreases in activity levels. Also, the concomitant administration of GH and CsA caused lowered production of 16␣-, 2␣-, 6␤-, and 2␤-hydroxytestosterone as compared with the administration of GH with CsA vehicle and as compared with the administration of GH vehicle with CsA. This study shows that GH is a dominating factor over CsA in determining hepatic P450 expression and activity. In addition, CsA does not seem to alter GH levels as a mediating event in suppressing P450 expression and activity. Since CsA given in combination with GH further suppressed P450 activity as compared with CsA given in combination with vehicle, this suggests that changes in hormonal status are likely to be one of the many factors that is responsible for the lack of a clear association between cyclosporine dosing and markers of toxicity.Immune suppression has been an effective avenue of treatment for several conditions including preventing organ transplantation rejection and autoimmune disease. One potent immunosuppressive drug, cyclosporine (CsA), a cyclic undecapeptide of fungal origin, is often used as the drug of choice following organ transplantation. CsA is mainly used for the prevention of allograft rejection and for the prevention of graft-versus-host disease following a bone marrow transplant, as well as for the treatment of arthritis (Tugwell et al., 1987). Although CsA is known to affect interleukins 3 and 4 (IL-3, IL-4), tumor necrosis factor-␣, and B cells, it primarily imparts its immunosuppressive action by preventing IL-2 synthesis from activated T cells (Bunjes et al., 1981).Despite the effectiveness of CsA in suppressing the immune response, there exist several potentially harmful side effects, including nephrotoxicity, hepatotoxicity, and hypertension (Borel, 1990). Since CsA is not only a substrate, but also an inhibitor of CYP3A2, it can modify hepatic drug metabolism in rats following chronic therapy (Brunner et al., 1996). CsA suppresses cytochrome P450 (P450) protein expression, which could then hinder further metabolism of CsA (Cunningham et al., 1985;Brunner et al...

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The Regulation by Growth Hormone of Microsomal Testosterone 6β-Hydroxylase in Male Rat Livers1

Cited by 49 publications

References 0 publications

Interspecies homology of cytochrome P-450: Inhibition by anti-P-450-Male antibodies of testosterone hydroxylases in liver microsomes from various animal species including man.

Interspecies homology of cytochrome P-450: Inhibition by anti-P-450-Male antibodies of testosterone hydroxylases in liver microsomes from various animal species including man.

Localization and Age-Related Changes in Cytochrome P450 Expression in APA Hamster Livers.

Suppression of Hepatic CYP3A1/2 and CYP2C11 by Cyclosporine Is Not Mediated by Altering Growth Hormone Levels

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