What knockout mice can tell us about parturition.
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Many molecules, including steroid and peptide hormones, prostaglandins and cytokines, regulate the preparation, initiation and progression of parturition in mammals. Gene targeting studies show that, in the knockout mice of steroid 5alpha-reductase type 1 gene, prostaglandin F2alpha receptor gene and cytosolic phospholipase A2 gene, parturition was severely disturbed, although live offspring were delivered by Caesarean section. Relaxin gene-disrupted mice also showed protracted labour. However, most knockout mice in which the steroid hormone, prostaglandin, cytokine or peptide hormone (for example, oxytocin, corticotrophin releasing hormone and endothelin) endocrine-paracrine systems are disrupted are inadequate for analysis of the mechanism of parturition because they die before reaching reproductive age or are infertile, or because they reproduce normally. A conditional knockout strategy, for example, using the Cre-LoxP system, should be considered for investigating the biochemical background of parturition to overcome these problems. (+info)
Cortisol effects on body mass, blood pressure, and cholesterol in the general population.
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The effects of excess cortisol secretion on blood pressure and fat deposition are well documented, but the importance of this glucocorticoid in controlling these processes in normal individuals is less clear. We studied the relationship between cortisol excretion rate (tetrahydrocortisol [THF]+allo-THF+tetrahydrocortisone [THE]) and a range of important cardiovascular risk factors in 439 normal subjects (238 male) sampled from the North of Glasgow (Scotland) population. There were marked gender differences: female subjects were lighter and had lower blood pressures and cortisol levels, whereas HDL cholesterol was higher. The pattern of cortisol metabolism was also different; the index of 11beta-hydroxysteroid dehydrogenase activity (THF+allo-THF/THE) was lower and that of 5alpha-reductase (allo-THF/THF) was higher. There was a strong correlation of blood pressure (positive), cholesterol (positive), and HDL cholesterol (negative in women, positive in men) with age. Cortisol excretion rate did not correlate with blood pressure but correlated strongly with parameters of body habitus (body mass index and waist and hip measurements [positive]) and HDL cholesterol (negative). With multiple regression analysis, there remained a significant association of cortisol excretion rate with HDL cholesterol in men and women and with body mass index in men. These results suggest that glucocorticoids regulate key components of cardiovascular risk. (+info)
Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'-methylhydroxylation by quinidine and hydroquinidine in vitro.
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In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased Km and increased Vmax of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both Km and Vmax of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations. (+info)
Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2).
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Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk. (+info)
Male and female isoenzymes of steroid 5alpha-reductase.
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There are two steroid 5alpha-reductase isoenzymes, designated type 1 and type 2, in mammals and recent experiments show that each plays a unique physiological role. In this article, the hypothesis is developed that the type 1 gene specifies a female isoenzyme, whereas the type 2 gene specifies a male isoenzyme. This idea results from the following observations. First, mutation of the 5alpha-reductase type 1 gene in mice affects reproduction in females by decreasing fecundity and blocking parturition, but has no effect on reproduction in males. Second, mutation of the 5alpha-reductase type 2 gene in mice and men prevents proper virilization but does not affect development or reproductive function in females. Analyses of these diverse phenotypes indicate that the isoenzymes catalyse both anabolic and catabolic reactions in steroid hormone metabolism. (+info)
No mutations found in candidate genes for dystocia.
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Dystocia is a disorder characterized by prolonged or dysfunctional labour. Delivery that starts late or not at all, leads to an increased risk for Caesarean section, infant morbidity and mortality. Familial aggregations of dystocia suggest a polygenic background. We have studied three candidate genes for dystocia, i.e. the genes for testosterone 5-alpha reductase type 1, prostaglandin F2alpha receptor and endothelin 1 and performed mutational screening in 23 women with dystocia, of which 12 have affected relatives. No mutations were found, making it unlikely that any of these genes represent a major cause of dystocia in man. (+info)
Modulation of hepatic CYP2A1, CYP2C11, and CYP3A9 expression in adult rats by neonatal administration of tamoxifen.
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To examine the effect of neonatal administration of tamoxifen on adult expression of hepatic cytochrome P-450 (CYP) enzymes and steroid 5alpha-reductase, male and female Sprague-Dawley rats were injected s.c. with tamoxifen (20 microg) or peanut oil (control) once daily at days 1 to 5 of age and sacrificed at 3 months of age. Neonatal tamoxifen treatment did not affect b.wt. or liver weight of adult male and female rats, but decreased testicular weight by approximately 40% in adult male rats. Neonatal administration of tamoxifen decreased hepatic microsomal testosterone 6beta- and 7alpha-hydroxylase activities in adult female rats whereas it did not alter steroid 5alpha-reductase activity. The same treatment increased testosterone 7alpha-hydroxylase activity, but did not affect testosterone 6beta-hydroxylase or steroid 5alpha-reductase activity in adult male rats. Immunoblot analysis indicated that neonatal tamoxifen treatment decreased CYP2C11 protein level by 26% and increased CYP2A1 protein content by 2.6-fold in adult male rats, whereas it had no effect on CYP3A or CYP2B protein expression. The reduction in the CYP3A-mediated testosterone 6beta-hydroxylase activity in adult female rats was accompanied by a decrease in CYP3A9 mRNA expression. Analysis of serum hormone levels indicated that neonatal exposure to tamoxifen resulted in a decrease in serum 17beta-estradiol concentration in adult female rats, whereas it did not alter serum testosterone concentration in adult male rats. In summary, treatment of neonatal rats with tamoxifen produced a long-lasting effect on hepatic CYP2A1, CYP2C11, and CYP3A9 expression in addition to testicular weight and serum 17beta-estradiol concentration. (+info)
The V89L polymorphism in the 5alpha-reductase type 2 gene and risk of prostate cancer.
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5alpha-Reductase type 2, the predominant prostatic isozyme of this protein, converts testosterone to dihydrotestosterone. It has been hypothesized that individuals with greater 5alpha-reductase activity are at increased risk for prostate cancer (CaP). A single nucleotide polymorphism of the 5alpha-reductase type 2 gene (SRD5A2) gives rise to a substitution of leucine (leu) for valine (val) at codon 89 (V89L), the presence of which may affect serum androstanediol glucuronide (AAG) levels. We studied the effect of this polymorphism on the risk of prostate cancer in a prospective, nested, case-control design within the Physicians' Health Study. In all controls (n = 799), the leu allele frequency was 0.30. Among the 386 controls with plasma AAG levels available, there was no significant association between AAG levels and V89L genotype. We also detected no significant association between risk for CaP and genotype [odds ratio: val/val = 1.0 (reference), leu/val = 0.96 (95% confidence interval, 0.76-1.20), and leu/ leu = 0.84 (95% confidence interval, 0.57-1.24)]. These data do not support a moderate to large effect of the SRD5A2 V89L polymorphism on plasma AAG levels or CaP risk in this predominantly Caucasian cohort, although a small effect cannot be completely excluded. (+info)