Toxic effects of triptolide on adrenal steroidogenesis in H295R cells and female rats

2019 ◽  
Vol 33 (11) ◽  
Author(s):  
Ling‐Yan Xu ◽  
Wei Wu ◽  
Rui Cheng ◽  
Li‐Xin Sun ◽  
Zhen‐Zhou Jiang ◽  
...  
Keyword(s):  
Female Rats ◽  
Toxic Effects ◽  
Adrenal Steroidogenesis ◽  
H295r Cells

scholarly journals ACUTE AND SUB CHRONIC TOXICITY STUDIES OF PURIFIED WITHANIA SOMNIFERA EXTRACT IN RATS

2018 ◽  
Vol 10 (12) ◽  
pp. 41 ◽  
Author(s):  
Benny Antony ◽  
Merina Benny ◽  
Binu T. Kuruvilla ◽  
Nishant Kumar Gupta ◽  
Anu Sebastian ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Dose Level ◽  
Chronic Toxicity ◽  
Withania Somnifera ◽  
Clinical Signs ◽  
Repeated Administration ◽  
Female Rats ◽  
Toxic Effects ◽  
Toxicity Studies ◽  
Adverse Effect Level

Objective: The objective of the present study was to evaluate the acute and sub-chronic (90 d; repeated dose) toxicity of Withania somnifera (ashwagandha) extract in rats.Methods: The acute toxicity was evaluated as per OECD (Organisation for Economic Co-operation and Development) guidelines 423. Purified ashwagandha extract (PAE) was fed at 2000 mg/kg body weight (bw) to overnight fasted female rats. The animals were observed daily for clinical signs of abnormality/mortality. After 14 d, animals were sacrificed and gross pathological changes were recorded. Sub-chronic toxicity of PAE was studied by feeding the extract at 100, 500 and 1000 mg/kg bw daily to rats as per OECD guidelines 408. After 90 d feeding, heamatological and biochemical parameters of treated rats were compared with control animals. Histopathology of all the major organs was also studied.Results: In the acute toxicity study, no mortality or clinical signs of toxicity were observed in any of the animals at maximum recommended dose level of 2000 mg/kg bw; therefore the LD50 is>2000 mg/kg bw in rats. The repeated administration of PAE for 90 d in rats at the maximum dose level of 1000 mg/kg bw did not induce any observable toxic effects, when compared to its corresponding control animals. The hematology and biochemistry profile of treated rats was similar to control animals and difference was non-significant (p>0.05). The histopathology of major organs of all the control and treated animals was normal. In this study the NOAEL (No Observed Adverse Effect Level) was calculated as 1000 mg/kg bw daily for rats.Conclusion: The present study clearly indicates that PAE does not have any toxic effects in animals at the dose evaluated as evidenced by acute and sub chronic toxicity studies in rats.

scholarly journals Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities

2007 ◽  
Vol 195 (3) ◽  
pp. 459-472 ◽  
Author(s):  
Elika Samandari ◽  
Petra Kempná ◽  
Jean-Marc Nuoffer ◽  
Gaby Hofer ◽  
Primus E Mullis ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Cell Lines ◽  
Cytochrome B5 ◽  
Hydroxysteroid Dehydrogenase ◽  
Adrenal Steroidogenesis ◽  
Steroid Profile ◽  
Lyase Activity ◽  
H295r Cells ◽  
Species Specific

The human adrenal cortex produces mineralocorticoids, glucocorticoids, and androgens in a species-specific, hormonally regulated, zone-specific, and developmentally characteristic fashion. Most molecular studies of adrenal steroidogenesis use human adrenocortical NCI-H295A and NCI-H295R cells as a model because appropriate animal models do not exist. NCI-H295A and NCI-H295R cells originate from the same adrenocortical carcinoma which produced predominantly androgens but also smaller amounts of mineralocorticoids and glucocorticoids. Research data obtained from either NCI-H295A or NCI-H295R cells are generally compared, although for the same experiments no direct comparison between the two cell lines has been performed. Therefore, we compared the steroid profile and the expression pattern of important genes involved in steroidogenesis in both cell lines. We found that steroidogenesis differs profoundly. NCI-H295A cells produce more mineralocorticoids, whereas NCI-H295R cells produce more androgens. Expression of the 3β-hydroxysteroid dehydrogenase (HSD3B2), cytochrome b5, and sulfonyltransferase genes is higher in NCI-H295A cells, whereas expression of the cytochrome P450c17 (CYP17), 21-hydroxylase (CYP21), and P450 oxidoreductase genes does not differ between the cell lines. We found lower 3β-hydroxysteroid dehydrogenase type 2 but higher 17,20-lyase activity in NCI-H295R cells explaining the ‘androgenic’ steroid profile for these cells and resembling the zona reticularis of the human adrenal cortex. Both cell lines were found to express the ACTH receptor at low levels consistent with low stimulation by ACTH. By contrast, both cell lines were readily stimulated by 8Br-cAMP. The angiotensin type 1 receptor was highly expressed in NCI-H295R than NCI-H295A cells and angiotensin II stimulated steroidogenesis in NCI-H295R but not NCI-H295A cells. Our data suggest that comparative studies between NCI-H295A and NCI-H295R cells may help find important regulators of mineralocorticoid or androgen biosynthesis.

scholarly journals Inhibitors of oestrogen biosynthesis: preclinical studies with CGS 16949A, a new nonsteroidal aromatase inhibitor

1989 ◽  
Vol 95 ◽  
pp. 293-303 ◽  
Author(s):  
Ajay S. Bhatnagar ◽  
Klaus Schieweck ◽  
Albert Häusler ◽  
Leslie J. Browne ◽  
Ronald E. Steele
Keyword(s):  
Aromatase Inhibitor ◽  
Oral Treatment ◽  
Female Rats ◽  
Complete Regression ◽  
Adrenal Steroidogenesis ◽  
Effective Doses ◽  
Glucocorticoid Production ◽  
Oestrogen Deprivation

SynopsisInhibitors of the aromatase enzyme represent a class of therapeutic agents which potently inhibit oestrogen biosynthesis in vivo. This inhibition of oestrogen biosynthesis is well established as effective therapy in the treatment of oestrogen-dependent breast cancer. CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[l,5-a]pyridin-5-yl)-benzonitrile hydrochloride] is a non-steroidal imidazole derivative which is a potent competitive aromatase inhibitor in vitro. At a maximally effective concentration, it selectively inhibits aromatase and does not affect glucocorticoid production from the adrenal in vitro.In vivo in the rat, CGS 16949A effectively reduces ovarian oestrogen content and potently inhibits an aromatase-mediated androgen-induced uterine hypertrophy. Oral treatment of adult, cyclic female rats with CGS 16949A disrupts cyclicity, inhibits ovulation, reduces uterine weight and suppresses serum oestradiol, all expected sequelae of oestrogen deprivation. At maximally effective doses, there is no evidence of adrenal hypertrophy, indicating that adrenal steroidogenesis is unaffected. In the DMBA-induced mammary carcinoma model in the rat, CGS 16949A caused almost complete regression of palpable tumours and significantly suppressed the appearance of new tumours at a maximally effective oral dose. Thus, CGS 16949A is a potent and selective inhibitor of the aromatase enzyme. In the rat, it is very efficacious in inhibiting oestrogen biosynthesis and in suppressing the growth of DMBA-induced mammary tumours.

EFFECTS OF TESTOSTERONE ON PITUITARY CORTICOTROPHIN AND ADRENAL STEROID SECRETION IN MALE AND FEMALE RATS

1963 ◽  
Vol 43 (4) ◽  
pp. 601-608 ◽  
Author(s):  
Julian I. Kitay
Keyword(s):  
Plasma Corticosterone ◽  
Female Rats ◽  
Male Rats ◽  
Intact Male ◽  
Male And Female ◽  
Adrenal Steroid ◽  
Adrenal Steroidogenesis ◽  
Male And Female Rats

ABSTRACT Administration of a depot testosterone preparation to male and female rats resulted in no change in body or pituitary weight in either sex. Pituitary corticotrophin content was unaltered in male animals but was reduced in females. Adrenal weights and adrenal RNA and DNA contents were decreased in both sexes. Plasma corticosterone concentrations were unaffected in males but were reduced in female rats after stress or corticotrophin injection. Hepatic reduction of ring A in vitro and biological half-life of corticosterone in vivo were unchanged in male animals but impaired in females. Testosterone administration to intact male rats significantly increased adrenal steroidogenesis measured in vitro. A significant decrease in steroid production was found in intact females but increased steroidogenesis was observed in adrenals from testosterone-treated oophorectomized animals. No effect was obtained following addition of testosterone directly in vitro. The data suggest that testosterone leads both to diminution of corticotrophin secretion and enhancement of adrenal steroid secretory capacity. In intact female rats, these effects are complicated by suppression of oestrogen secretion, the effects of which have been reported previously.

Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis

2007 ◽  
Vol 30 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Damian G. Romero ◽  
Silvia Rilli ◽  
Maria W. Plonczynski ◽  
Licy L. Yanes ◽  
Ming Yi Zhou ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Function ◽  
Cortical Cell ◽  
Regulatory Genes ◽  
Cell Physiology ◽  
Aldosterone Synthase ◽  
Adrenal Steroidogenesis ◽  
Extracellular Stimuli ◽  
Reporter Assays ◽  
H295r Cells

Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled to respond to extracellular stimuli. We studied transcription regulatory genes modulated by angiotensin II, one of the most important regulators of adrenal cortical cell function, and their role in adrenal steroidogenesis in H295R human adrenocortical cells. Angiotensin II-modulated transcription regulatory genes were identified with high-density oligonucleotide microarrays and the results validated by real-time RT-PCR. Cotransfection reporter assays were performed in H295R cells to analyze the role of these transcription regulatory genes in the control of the expression of 11β-hydroxylase and aldosterone synthase, the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, respectively. We selected a subset of the most regulated genes for reporter plasmid studies to determine the effect on these enzymes. BHLHB2, BTG2, and SALL1 decreased expression of both enzymes, whereas CITED2, EGR2, ELL2, FOS, FOSB, HDAC5, MAFF, MITF, NFIL3, NR4A1, NR4A2, NR4A3, PER1, and VDR increased expression for both enzymes. By the ratio of aldosterone synthase to 11β-hydroxylase expression, NFIL3, NR4A1, NR4A2, and NR4A3 show the greatest selectivity toward upregulating expression of the mineralocorticoid biosynthetic pathway preferentially. In summary, this study reports for the first time a set of transcription regulatory genes that are modulated by angiotensin II and their role in adrenal gland steroidogenesis. Abnormal regulation of the mineralocorticoid or glucocorticoid biosynthesis pathways is involved in several pathophysiological conditions; hence the modulated transcription regulatory genes described may correlate with adrenal steroidogenesis pathologies.

scholarly journals The subchronic toxic effects of Mosla Chinensis Maxim in normal rats.

2020 ◽  
Author(s):  
Dan Lei ◽  
Longxue Li ◽  
Shenghong Huang ◽  
Li Liu ◽  
Pingdong Cai ◽  
...  
Keyword(s):  
Dose Group ◽  
Intestinal Flora ◽  
Female Rats ◽  
Toxic Effects ◽  
Fixed Dose ◽  
Control Group ◽  
Subchronic Toxicity ◽  
Male And Female ◽  
Sd Rats

Abstract Background: The aim of this work was to study the toxic effects and target organs of Mosla Chinensis Maxim (MCM) in rats and provide theoretical basis for clinical medication.Methods: The subchronic toxicity study was conducted on 60 male and female SD rats using the fixed-dose method for the treatment group and 20 male and female SD rats for the control. At the subchronic toxicity study, the water extract of MCM with fixed-dose of 0.2g/kg/day, 2g/kg/day and 20g/kg/day was administered for 90 days intragastric, and the control group was given the same amount of distilled water. After 90 days, the general conditions of the rats were observed. Assesment on safety of the extract was conducted by a subchronic toxicity test which mainly examined alteration occured in gut flora and urine metabolism. Results: The results showed that there were no significant toxic effects observed at all doses on physical sign and reactivity and fecal property of rats in the treatment groups had no obvious difference from those in control group. The results of routine blood test showed that the number of red blood cells in the male medium dose group and the female low dose group were significantly different from those in the control group (P<0.05). The results of serum biochemical indicators test showed that MCM had influence on the indicators of liver and kidney function, but it had no toxicological significance. In terms of glucose and lipid metabolism, the LDL level of male rats was lower than that of the control group (P<0.05). Compared with the control group, GLU level of female rats in the low, medium and high dose groups was significantly increased (P<0.05), indicating that long-term administration of MCM would affect the glucose level of female rats. The results of intestinal flora diversity showed that feeding MCM for 90 days had an impact on the distribution of intestinal flora. The content of lactobacillus increased and the ratio of Firmicutes and Bacteroidetes (F/B) was also affected, but there was no significant difference. Conclusions: These findings showed that the long-term intragastric administration of the MCM is safe to use within its dose recommendation. But it could have slight affect the metabolism of uric acid by changing the composition of intestinal flora and affecting the metabolism of tryptophan.

Toxic effects of chromium (VI) by maternal ingestion on liver function of female rats and their suckling pups

2011 ◽  
Vol 28 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Nejla Soudani ◽  
Hanen Bouaziz ◽  
Mediha Sefi ◽  
Yassine Chtourou ◽  
Tahia Boudawara ◽  
...  
Keyword(s):  
Liver Function ◽  
Female Rats ◽  
Toxic Effects ◽  
Chromium Vi

Hypocretin/orexin increases the expression of steroidogenic enzymes in human adrenocortical NCI H295R cells

2009 ◽  
Vol 297 (5) ◽  
pp. R1601-R1609 ◽  
Author(s):  
Jan Wenzel ◽  
Nicole Grabinski ◽  
Cordula A. Knopp ◽  
Andreas Dendorfer ◽  
Manjunath Ramanjaneya ◽  
...  
Keyword(s):  
Adrenal Glands ◽  
Synthesis Rate ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Steroidogenic Enzymes ◽  
Orexin A ◽  
Orexin Receptors ◽  
Adrenal Steroidogenesis ◽  
Intracellular Ca ◽  
H295r Cells

Hypocretins/orexins act through two receptor subtypes: OX1 and OX2. Outside the brain, orexin receptors are expressed in adrenal glands, where orexins stimulate the release of glucocorticoids. To further address the regulation of steroidogenesis, we analyzed the effect of orexins on the expression of steroidogenic enzymes in human adrenocortical National Cancer Institute (NCI) H295R cells by qPCR. In NCI H295R cells, OX2 receptors were highly expressed, as they were in human adrenal glands. After treatment of NCI H295R cells with orexin A for 12–24 h, the cortisol synthesis rate was significantly increased, whereas 30 min of treatment showed no effect. While CYP11B1 and CYP11B2 mRNA levels were increased already at earlier time points, the expression of HSD3B2 and CYP21 mRNA was significantly up-regulated after treatment with orexin A for 12 h. Likewise, orexin B increased CYP21 and HSD3B2 mRNA levels showing, however, a lower potency compared with orexin A. The mRNA levels of CYP11A and CYP17 were unaffected by orexin A. OX2 receptor mRNA levels were down-regulated after 12 and 24 h of orexin A treatment. Orexin A increased intracellular Ca2+ but not cAMP concentrations in NCI H295R cells. Furthermore, inhibition of PKC and MAPK kinase/ERK kinase (MEK1/2) prevented the increase of HSD3B2 expression by orexin A. Accordingly, orexin A treatment of NCI H295R cells markedly enhanced ERK1/2 phosphorylation that was prevented by PKC and, in part, PKA inhibition. In conclusion, orexins may influence adrenal steroidogenesis by differential regulation of the expression of steroidogenic enzymes involving Ca2+, as well as PKC-ERK1/2 signaling.

Final Report on the Safety Assessment of BHT

2002 ◽  
Vol 21 (2_suppl) ◽  
pp. 19-94 ◽  
Keyword(s):  
Butylated Hydroxytoluene ◽  
Female Rats ◽  
Toxic Effects ◽  
Male Rats ◽  
Skin Tests ◽  
Oral Exposure ◽  
Clinical Test ◽  
Number Of Patients ◽  
Wide Range ◽  
Cosmetic Formulations

BHT is the recognized name in the cosmetics industry for butylated hydroxytoluene. BHT is used in a wide range of cosmetic formulations as an antioxidant at concentrations from 0.0002% to 0.5%. BHT does penetrate the skin, but the relatively low amount absorbed remains primarily in the skin. Oral studies demonstrate that BHT is metabolized. The major metabolites appear as the carboxylic acid of BHT and its glucuronide in urine. At acute doses of 0.5 to 1.0 g/kg, some renal and hepatic damage was seen in male rats. Short-term repeated exposure to comparable doses produced hepatic toxic effects in male and female rats. Subchronic feeding and intraperitoneal studies in rats with BHT at lower doses produced increased liver weight, and decreased activity of several hepatic enzymes. In addition to liver and kidney effects, BHT applied to the skin was associated with toxic effects in lung tissue. BHT was not a reproductive or developmental toxin in animals. BHT has been found to enhance and to inhibit the humoral immune response in animals. BHT itself was not generally considered genotoxic, although it did modify the genotoxicity of other agents. BHT has been associated with hepatocellular and pulmonary adenomas in animals, but was not considered carcinogenic and actually was associated with a decreased incidence of neoplasms. BHT has been shown to have tumor promotion effects, to be anticarcinogenic, and to have no effect on other carcinogenic agents, depending on the target organ, exposure parameters, the carcinogen, and the animal tested. Various mechanism studies suggested that BHT toxicity is related to an electrophillic metabolite. In a predictive clinical test, 100% BHT was a mild irritant and a moderate sensitizer. In provocative skin tests, BHT (in the 1% to 2% concentration range) produced positive reactions in a small number of patients. Clinical testing did not find any depigmentation associated with dermal exposure to BHT, although a few case reports of depigmentation were found. The Cosmetic Ingredient Review Expert Panel recognized that oral exposure to BHT was associated with toxic effects in some studies and was negative in others. BHT applied to the skin, however, appears to remain in the skin or pass through only slowly and does not produce systemic exposures to BHT or its metabolites seen with oral exposures. Although there were only limited studies that evaluated the effect of BHT on the skin, the available studies, along with the case literature, demonstrate no significant irritation, sensitization, or photosensitization. Recognizing the low concentration at which this ingredient is currently used in cosmetic formulations, it was concluded that BHT is safe as used in cosmetic formulations.

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