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PubMed1999

Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region.

Cytochrome P450 3A4, the most abundant P450 form in human liver, exhibits a very broad substrate specificity and is of great importance for drug metabolism. The interindividual difference in the hepatic expression of CYP3A4 is considerable. In order to investigate possible genetic factor(s) causing this variation, the rate of 6beta-hydroxylation of testosterone in human liver microsomes prepared from 46 different human liver samples was determined and the 5'upstream region (+10 to -490 bp) was sequenced from genomic DNA isolated from 39 of these livers. We found a 31-fold variation of the testosterone hydroxylase activity between the samples. However, a very high sequence homology between the CYP3A4 5'-upstream regions sequenced from the 78 different alleles was found. In fact, only three variant nucleotide exchanges were identified, all causing a -290 A-->G mutation (CYP3A4-V) in a so called nifedipine specific element (NFSE). The importance of this element and the polymorphism was evaluated by gel shift analysis. Competition experiments revealed that the binding of nuclear proteins, although having lower affinity to the CYP3A4-V form of the element, was unspecific in nature. In accordance, no influence of this polymorphism was seen on the microsomal testosterone hydroxylase activity in vitro. It is concluded that the promoter region of CYP3A4 is highly conserved, the only polymorphism being in the NFSE, which however does not influence the enzyme expression in liver to a significant degree. This casts doubt of a previously described relationship between the CYP3A4-V allele and cancer in the prostate and leukaemia.

Adolescent↗
PubMed2000

Sex steroid influence on cannabinoid CB(1) receptor mRNA and endocannabinoid levels in the anterior pituitary gland.

Recent studies have demonstrated the occurrence of endocannabinoid synthesis and of gene expression and immunoreactivity for the cannabinoid CB(1) receptor in the anterior pituitary gland. Since the activity of this gland is under the influence of circulating sex steroids, the present study was designed to elucidate whether expression of the CB(1) receptor gene in the anterior pituitary gland is also under the influence of these steroids. To this aim, we first examined the possible changes in the levels of CB(1) receptor-mRNA transcripts in the anterior pituitary gland of intact male rats and normal cycling female rats at the different stages of the ovarian cycle. We observed that males had higher levels of CB(1) receptor-mRNA transcripts than females. In addition, these transcripts fluctuated in females during the different phases of the ovarian cycle, with the highest values observed on the second day of diestrus and the lowest on estrus. In these animals, we also measured the content of endocannabinoids in the anterior pituitary gland and the hypothalamus. We observed that females had higher contents of anandamide than males in both cases. The content of anandamide in females also fluctuated during the ovarian cycle in both the anterior pituitary gland and the hypothalamus. The highest values in the anterior pituitary gland were found in the estrus and the lowest on the first day of diestrus and proestrus, whereas the inverse tendency was found in the hypothalamus. No changes were observed in the other major endocannabinoid, 2-arachidonoyl-glycerol, between males and females and during the ovarian cycle. To further explore the potential influence of circulating sex steroids on CB(1) receptor gene expression in the anterior pituitary gland, as a second objective, we examined the possible changes in the amount of transcripts for this receptor in gonadectomized and sex steroid-replaced gonadectomized rats of both sexes. We observed that orchidectomy (ORCHX) in males reduced CB(1) receptor-mRNA levels, whereas replacement with dihydrotestosterone also maintained low levels of this messenger. In females, estradiol-replaced ovariectomized (OVX) rats exhibited significantly lower CB(1) receptor-mRNA levels than OVX animals that had not been replaced with this estrogen. In this experiment, we also examined if the previously reported response of the CB(1) receptor gene in the anterior pituitary lobe to chronic administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is under sex steroid influence. We observed that chronic Delta(9)-THC treatment decreased CB(1) receptor-mRNA levels in intact and ORCHX males, but not in dihydrotestosterone-replaced ORCHX males. In females, Delta(9)-THC treatment produced no effect in both OVX- and estradiol-replaced OVX rats. In summary, these data collectively support that expression of the CB(1) receptor gene in the anterior pituitary gland is regulated by sex steroids in both males and females. Furthermore, gonadal steroids appear to affect the response of this gene to chronic cannabinoid administration. We have also observed that anandamide contents in the anterior pituitary gland and the hypothalamus might be controlled by circulating sex steroids. The functional implications of these data are discussed.

Animals↗
PubMed2000

Changes in the metabolic elimination profile of testosterone following exposure of the crustacean Daphnia magna to tributyltin.

The biocide tributyltin has been found to cause the development of pseudohermaphroditic conditions in some neogastropod species. These abnormalities of the reproductive system have adversely affected the fecundity of some field populations of gastropods, resulting in local population declines. Current evidence suggests that tributyltin elicits these effects by interfering with the biotransformation of testosterone to other steroid derivatives, resulting in an elevation in endogenous testosterone or some of its bioactive derivatives. The purpose of the present study was to determine whether tributyltin altered testosterone metabolism in daphnids (Daphnia magna), a species commonly used in ecotoxicology testing. Exposure of daphnids to 1.2 microg (tin)/L caused a general increase in the rate of elimination of oxido-reduced, hydroxylated, and glucose-conjugated derivatives of testosterone. However, tributyltin exposure had no significant effect on the rate of elimination of the glucose-conjugated forms of the various oxido-reduced and hydroxylated derivatives of testosterone. As a result, the percentage of the oxido-reduced and hydroxylated metabolites of testosterone eliminated as glucose conjugates decreased with increasing tributyltin exposure levels. These results demonstrate that tributyltin causes alterations in testosterone metabolism in daphnids that would result in an increase in the production of oxido-reduced derivatives. These products are preferentially retained in the tissues of daphnids and are variously androgenic in vertebrates. The increased production of oxido-reduced derivatives of testosterone may be mechanically responsible for the masculinizing effects of tributyltin in some species and suggests that daphnids may be a suitable surrogate for evaluating the potential of chemicals to elicit this form of toxicity.

Androstane-3,17-diol↗
PubMed1993

Sex steroid levels in Porichthys notatus, a fish with alternative reproductive tactics, and a review of the hormonal bases for male dimorphism among teleost fishes.

Plasma levels of 11-ketotestosterone, 11-beta-OH-testosterone, testosterone, and 17-beta-estradiol were measured in reproductive Porichthys notatus, a teleost fish with two male morphs and alternative reproductive tactics. The two male types had contrasting androgen profiles. 11-Ketotestosterone was the predominant androgen in the Type I male morph which acoustically courts females, excavates nests, and guards eggs. Yet testosterone was predominant in the plasma of the Type II male morph which neither courts females nor nests, but instead parasitizes Type I males with sneak or satellite spawning tactics. The Type I-Type II male divergence in reproductive tactics and androgen levels is paralleled by dimorphisms in the vocal system, in body size, and in relative testis size. A review of endocrine data from six different species with male dimorphism shows consistent differences between morphotypes and a striking pattern: 11-ketotestosterone levels are uniformly elevated in each "courting male" morphotype relative to its "noncourting" conspecific. This cross-species pattern may reflect the behavioral, gonadal, or morphological differences which characterize the two morphotypes. At this point, the morphological interpretation is favored.

Animals↗
PubMed1992

Effects of cyclosporins and transforming growth factor beta 1 on thyroid hormone action in cultured fetal rat limb bones.

To study the mechanism of action of thyroid hormones on bone, we examined the effects of immunosuppressive and nonimmunosuppressive cyclosporins, as well as of transforming growth factor beta 1 (TGF beta 1), 17 beta-estradiol (E2), and dihydroxytestosterone (DHT) on thyroxine (T4)- and triiodothyronine (T3)-stimulated bone resorption in fetal rat limb bones. The immunosuppressive cyclosporins A (CsA) and G (CsG) inhibited thyroid hormone (T4 + T3)-stimulated resorption and beta-glucuronidase release into the culture medium, whereas the weak or nonimmunosuppressive cyclosporins D (CsD) and H (CsH) did not show this effect. Increasing the medium calcium concentration reduced the ability of T4 to stimulate 45Ca release, while not significantly affecting the response to CsA. TGF beta 1 elicited a biphasic effect when administered together with T4. During the first 3 days of culture, TGF beta 1 elicited a small, nonsignificant decrease in released 45Ca; during a subsequent 3 days of culture, it enhanced T4-stimulated bone resorption significantly. These effects differed from those of TGF beta 1 on parathormone-stimulated resorption. E2 and DHT did not influence the action of T4 on bone tissue. These results suggest that the mechanism of action of thyroid hormones on bone may involve immune factors, as well.

Animals↗
PubMed2006

Quantitative prediction of macrolide drug-drug interaction potential from in vitro studies using testosterone as the human cytochrome P4503A substrate.

OBJECTIVE: Macrolide antibiotics are mechanism-based inactivators of CYP3A enzymes that exhibit varying degrees of inhibitory potency. Our aim was to predict quantitatively the drug-drug interaction (DDI) potential of five macrolides from in vitro studies using testosterone as the CYP3A substrate, and to compare the predictions generated from human liver microsomal and recombinant CYP3A4 data. METHODS: The in vitro kinetic constants of CYP3A inactivation (K (I) and k (inact)) were estimated by varying the time of pre-incubation and the concentration of troleandomycin, erythromycin, clarithromycin, roxithromycin or azithromycin. CYP3A activity was determined from the measurement of testosterone 6beta-hydroxylation with human liver microsomes (HLM) and recombinant CYP3A4 as the enzyme sources. The mechanism-based pharmacokinetic model was fitted with inactivation data to predict the increase in oral area under the plasma concentration-time curve (AUC) for midazolam. RESULTS: All five macrolides inactivated testosterone 6beta-hydroxylation by HLM and recombinant CYP3A4 with k (inact) values in the range of 0.023 to 0.058 min(-1). The potency of inactivation (K (I)) was higher using recombinant CYP3A4 as the enzyme source. The oral AUCs for midazolam were predicted from HLM data to increase 16.6, 5.3, 4.6, 1.6 and 1.2-fold due to the inhibition of metabolic clearance by troleandomycin, erythromycin, clarithromycin, roxithromycin and azithromycin, respectively. These results are within the range of the AUC ratios reported for clinical DDI studies. The predicted AUC increases generated using recombinant CYP3A4 overestimated the magnitude of the DDIs. CONCLUSIONS: The DDI potential of five macrolide antibiotics was quantitatively predicted from in vitro studies using testosterone as the CYP3A substrate with HLM as the enzyme source.

Algorithms↗
PubMed1994

Catalytic roles of rat and human cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylations.

Differences in the catalytic roles of rat and human cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylase activities were examined. Liver microsomes from 18 human samples catalyzed coumarin 7-hydroxylation at a mean rate of about 60 pmol/min/nmol P450, but did not show any measurable activity for testosterone 7 alpha-hydroxylation. In rats, both activities were found to be developmentally regulated; 3-week-old rats had the highest activities for these two reactions. Anti-P450 2A1 antibodies and methoxsalen, a potent inhibitor of P450 2A-dependent monooxygenase activities in several animal species, inhibited almost completely both testosterone 7 alpha- and coumarin 7-hydroxylations catalyzed by liver microsomes prepared from 3-week-old male rats. Interestingly, although Km values for coumarin 7-hydroxylation activities in liver microsomes from 3-week-old rats were not different from those of adult humans, the Vmax value in rats was only 1/30 of that obtained in 18 human samples. Thus, the present results support the view that marked differences exist in the catalytic roles of rat and human P450 2A enzymes, which, in turn, may sometimes cause species-related differences in susceptibilities toward drug actions and toxicities.

Aging↗
PubMed1986

In vitro metabolism of steroid hormones in the liver and in blood cells of male rainbow trout (Salmo gairdneri Richardson).

Male rainbow trout show high plasma androgen levels beginning with the period of full spermatogenesis until the end of spermiation. The difficulties in explaining the steroid levels in regard to the concomitant changes of the plasma GTH concentrations prompted investigations into whether the steroid demand may be met in part by extragonadal steroid metabolism. The results of in vitro experiments with liver tissue fit into the concept of an interrenal-liver-gonad axis of androgen production, since increased amounts of C-19 steroids were detected in the media after incubation of hepatic tissue with cortisol. 17 beta-Hydroxysteroid dehydrogenase and hydroxysteroid glucuronyltransferase activities were shown to be associated with blood cells of mature males. The fact that unidentified products from incubations with 17 beta-estradiol, testosterone, and 17 alpha-hydroxyprogesterone were also found suggests that other steroid metabolizing enzymes are also associated with blood cells. The possibility is discussed that, assuming the blood cell activities are relevant in vivo, a production of potent androgens or the formation of water soluble steroid derivatives could proceed in the blood (e.g., 11-ketoandrostenedione----11-ketotestosterone; testosterone----testosterone glucuronide), possibly affecting the organism's steroid balance.

17-alpha-Hydroxyprogesterone↗
PubMed1987

Effect of gonadectomy and hypophysectomy on plasma steroid levels in male and female lampreys (Lampetra fluviatilis, L.).

Testosterone, estradiol, and dehydroepiandrosterone (T, E2, and DHA) were measured by RIA in plasma samples from three groups of sexually immature male and female (male, female) river lampreys: (I) intact, (II) gonadectomized, or (III) with pro- and mesoadenohypophysis removed (hypophysectomized). T levels were around 0.1 ng/ml in both I male and I female and increased significantly in all operated groups, especially in II male, to 1.2 ng/ml. E2 levels were between 0.7 and 1 ng/ml in I male and I female and were significantly elevated only in II male to 2.0 ng/ml. DHA levels showed significant decreases, from around 0.9 ng/ml in I male and I female, in both operated groups. It is suggested that T and E2 are secreted from a nongonadal source in both sexes and then converted to biologically active sex hormones in the gonads. Therefore T and E2 do not decrease, and may even accumulate, in the blood after gonadectomy. Since extirpation of the pro- and mesoadenohypophysis was not followed by a decrease in T and E2, their secretion may be stimulated by a hormone from another part of the pituitary such as the metaadenohypophysis.

Animals↗
PubMed1987

Serum androgens during the annual reproductive cycle of the male mummichog, Fundulus heteroclitus.

A technique for the simultaneous detection of serum concentrations of testosterone (T), 17 beta-hydroxy-4-androstene-3,11-dione (11-KT), and 11 beta, 17 beta-dihydroxy-4-androsten-3-one (11 beta-HT) was established using a combination of high performance liquid chromatography separation and radioimmunoassay. In the mummichog, Fundulus heteroclitus, serum concentrations of T, 11-KT, and 11 beta-HT varied from 11.3, 10.1, and 27.9 ng/ml, respectively, during the breeding season to 0.2, 0.3, and 0.9 ng/ml, respectively, during the nonbreeding season. The changes in serum androgen levels, determined weekly, did not coincide with changes in the gonosomatic index or measurement of sperm/gram testes. Increases in serum androgen levels did coincide with the rise in sperm index, but the decreases in serum concentrations of androgens preceded the fall in sperm index by more than a month. A model is proposed to explain the reproductive cycle of male mummichogs.

Androgens↗
PubMed1990

Hormonal sex manipulation and evidence for female homogamety in channel catfish.

The mechanism of sex determination in channel catfish Ictalurus punctatus was evaluated by hormonal and genetic methods. Aromatizable and nonaromatizable androgens, as well as an estrogen, caused feminization in fish fed steroids for 21 days after yolk-sac absorption. The effectiveness of 60 micrograms of ethynyltestosterone/g food decreased markedly when the experimental feeding period was shortened and was ineffective when the treatment lasted less than 12 days. Females from all-female populations produced by treatment with sex hormones were mated with normal males resulting in nine spawns with a sex ratio different from 1:1. The sex ratios were statistically similar to 3 male: 1 female in five spawns, both 2:1 and 3:1 in two spawns, and 2:1 in two spawns. These data are consistent with a model for female homogametic sex determination in channel catfish and suggest that the YY equivalent genotype is viable.

Administration, Oral↗