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

Abstract

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-

How Subchronic and Chronic Health Effects can be Neglected for GMOs, Pesticides or Chemicals

“…Sex-dependent differences in chronic diseases resulting from chemical intoxication are well established 18, 19. The liver is itself a sex-differentiated organ; for example chemical sensitivity is different in males and females 20. In Monsanto's data for these 3 month rat tests with Bt maize MON 863, for all rats including the six times bigger group of normal control and reference animals eating non GM diets, there were confirmed sex-differentiated effects in liver and kidneys parameters (Fig 2…”

Growth hormone replacement therapy induces codeine clearance

“…GH is an important regulator of drug and steroid metabolism in rats. The GH secretion shows marked sexual dimorphism, which leads to pronounced differences in steroid and drug metabolism [20–23]. High peaks in blood between almost undetectable baseline concentrations are profile characteristics in male rats in contrast to female rats, in which the peaks are more frequent and the baseline concentration is higher than in male rats [20,24].…”

Nuclear Receptor CAR Specifically Activates the Two-Pore K+ Channel Kcnk1 Gene in Male Mouse Livers, Which Attenuates Phenobarbital-Induced Hepatic Hyperplasia

“…Sexual dimorphic expressions of hepatic genes are often regulated by growth hormone and/or sex hormone secreted from the pituitary and gonadal gland, respectively (Ahluwalia et al, 2004;Erdstein et al, 1984;Kobliakov et al, 1991). First, we utilized hypophysectomized mice to examine whether or not the male-specific induction of KCNK1 by phenobarbital treatment depended on the pituitary gland.…”