Sexual Differentiation of Hepatic Steroid Metabolism in the Rat

Gustafsson, Jan‐Åke; Gustafsson, Sven A.; Ingelman‐Sundberg, Magnus; Pousette, Åke; Stenberg, Åke; Wränge, Örjan

doi:10.1016/b978-0-08-019709-8.50021-6

Cited by 10 publications

(14 citation statements)

References 12 publications

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“…Recently, evidence has been presented that the sexual differentiation of liver metabolism is controlled by the hypothalamo-hypophyseal system (3,4). This control seems to be exerted via the secretion of hypophyseal feminizing and possibly also by masculinizing factors, and at least some effects of estrogens and androgens upon liver metabolism are probably mediated via such factors (3,5).…”

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confidence: 97%

Partial Masculinization of Rat Liver Enzyme Activities Following Treatment with FSH

Gustafsson

Stenberg

1975

Endocrinology

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The metabolism of 4-(4014C)androstene-3,17-dione and 5alpha-(4-14C)androstene-3alpha, 17beta-diol was studies in the microsomal fraction and that of 4-(4-14C) androstene-3,17-dione in the 105,000 times g supernatant fraction of livers from castrated male and female rats treated with LH and FSH. Administration of LH led to significant decreases in 17-hydroxysteroid reduction and 7alpha-hydroxylation of 4-androstene-3,17-dione in both male and female rats and in 6beta-hydroxylation of 4-androstene-3,17-dione in female rats. FSH on the other hand specifically stimulated (masculinized) the following sex-dependent hydroxylations: 16alpha-hydroxylation of 4-androstene-3,17-dione in female rats and 2alpha-, and 2beta- and 18-hydroxylation of 5alpha-androstane-3alpha,17beta-diol in male rats. The metabolism of 4-androstene-3,17-dione and 5alpha-androstane-3alpha,17beta-diol was also studied in castrated male and female rats given testosterone propionate and in castrated female rats given testosterone propionate in combination with LH or FSH. It was shown that neither LH nor FSH could compensate for the relative androgen-unresponsiveness exhibited by female as compared to male rats. It is concluded that FSH but not LH may participate in the regulation of sex-dependent hydroxylase systems in rat liver.?2,Author

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confidence: 97%

Partial Masculinization of Rat Liver Enzyme Activities Following Treatment with FSH

Gustafsson

Stenberg

1975

Endocrinology

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“…The guinea pig liver system may fit the requirement as regards 16a-hydroxylase study. Its relative simplicity compared with species such as rat (19) and mouse (23), in which multiple hydroxylases are to be detected, commends it as a model. NOTE ADDED I N PROOF-Since submission of this paper we have established that our tentatively identified 6-hydroxy metabolites are 16P-hydroxy steroids.…”

Section: Discussionmentioning

confidence: 97%

“…In view of this, the major contribution of 16a-hydroxy steroids in the disulfate fraction formed by liver slices, even from free estrogens, is in line with the rapid sulfurylation of these latter. Gustafsson et al have demonstrated the profound effect of the sulfate moiety in directing steroid hydroxylationin rat (19) and human liver microsomes (20,21).…”

Section: Discussionmentioning

confidence: 98%

In vitro and in vivo studies on the metabolism of estrogens and their sulfates in guinea pigs

Hobkirk¹,

Freeman²,

Harvey³

et al. 1977

Can. J. Biochem.

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Labelled estradiol-17 beta(E2) or estrone (E1), when incubated with guinea pig liver slices, is metabolized by two main pathways. Part of each substrate is converted to estrone-3-glucuronide and estradiol-3-glucuronide. A further part of each is metabolized to estradiol-3-sulfate (E23S) and estrone-3-sulfate (E13S), which are interconverted. The latter conjugate appears to be the substrate for a 16 alpha-hydroxylase forming 16 alpha-hydroxyestrone-3-sulfate (16 alpha OHE13S). This, in turn, is further sulfurylated to yield 16 alpha-hydroxyestrone-3, 16-disulfate, accompanied by estriol-3,16-disulfate. A relatively small amount of tentatively indentified '6-hydroxyestrone disulfate accompanies these other two diconjugates. The guinea pig liver system suggests itself as a useful and relatively simple model for further study of 16 alpha-hydroxylation of E13S. The use of the latter as a natural subd E23S are present in liver, kidney, blood, gallbladder bile, intestine, uterus, and placenta after injection of labelled E2 into mature male and female guinea pigs. Some evidence has been obtained for the disulfate fraction (above) in liver and bile after injection of labelled E1.

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“…The catalytic specificity of the female isoform IIC12 (ice = 488.5 nm) is the ability to oxidize steroid sulfates in the position 158 [22,30,31]. However, the range of xenobiotics it oxidizes in the reconstituted enzyme system is not so wide as with isoform IICl1.…”

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confidence: 99%

Regulation of the expression of the sex‐specific isoforms of cytochrome P‐450 in rat liver

Кобляков¹,

Попова²,

Rossi

1991

European Journal of Biochemistry

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The hepatic metabolism of steroid hormones and of xenobiotics frequently depends on the expression of the sex-specific isoforms of cytochrome P-450 and on differences in sex hormones.Following biochemical, immunological and molecular biological investigations, it was shown that in adult rat liver there exist at least four male-specific and one female-specific isoforms of cytochrome P-450. The designation of these sex-specific genes is IIC11, IIIA2, IIC13 and IIA2 in males, and IIC12 in females. The irreversible programming of the expression of these isoforms of cytochrome P-450 in adulthood occurs during the perinatal period of life, and is named enzyme imprinting. One of the main factors that regulates the expression of the sexspecific isoforms of cytochrome P-450 is the level of androgens in the blood. Castration of adult rats decreased the level of the male isoforms of cytochrome P-450 and the activity of the monooxygenase enzyme system that remained higher than in intact females.The mechanism of enzyme imprinting can be explained as follows: neonatal androgens program the secretion of hypothalamic hormones, somatostatin and growth-hormone-releasing factor. These factors determine the type of growth hormone secretion in adult rats, and this controls the type of sex-specific isoforms of cytochrome P-450 expressed in adulthood.Metabolic regulation similar to that outlined above was shown to occur for several metabolism-dependent chemical carcinogens. Such a pathway may explain the different sensitivity displayed by male and female rats to treatment with these carcinogenic agents. One possible way of modulating the expression of some isoforms of cytochrome P-450 in adult rats is by treating neonates with specific xenobiotics that change the constitutive expression of neonatal androgens. It appears that this enzyme imprinting plays an important role in determining the individual sensitivity to the carcinogenic effects of chemicals.Most environmental compounds that are dangerous for health (carcinogens, mutagens, toxins) are indirectly acting agents and must be activated by the monooxygenase enzyme system in order to induce their effects in target tissues. The catalytic part of monooxygenases is cytochrome P-450, an enzyme highly concentrated in the liver, where the majority of xenobiotics are processed by either detoxification or activation metabolic pathways. It comprises a number of isoforms with overlapping substrate specificity. It is possible that the sensitivity of adult organisms to chemicals depends, among other factors, on the level of expression and substrate-specificity of these enzymes. The expression of some isoforms of the hepatic cytochrome P-450 in adulthood is programmed in the perinatal period of life, a type of regulation termed enzyme imprinting [l], also adopted to explain the sex-dependent regulation of xenobiotic metabolism in the liver.The purpose of this review is to provide an up-to-date description of the factors regulating the developmental im-

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Sexual Differentiation of Hepatic Steroid Metabolism in the Rat

Cited by 10 publications

References 12 publications

Partial Masculinization of Rat Liver Enzyme Activities Following Treatment with FSH

Partial Masculinization of Rat Liver Enzyme Activities Following Treatment with FSH

In vitro and in vivo studies on the metabolism of estrogens and their sulfates in guinea pigs

Regulation of the expression of the sex‐specific isoforms of cytochrome P‐450 in rat liver

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