The adrenocortical tumor cell line NCI-H295R as an in vitro screening system for the evaluation of CYP11B2 (aldosterone synthase) and CYP11B1 (steroid-11β-hydroxylase) inhibitors

Müller‐Vieira, Ursula; Angotti, Marc; Hartmann, Rolf W.

doi:10.1016/j.jsbmb.2005.04.032

Cited by 32 publications

(21 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Numerous recent studies have now evaluated this cell line and methodology as a rapid in vitro screening and mechanism elucidation tool, specifically for toxicant induced effects on steroidogenesis (e.g. Hilscherova et al, 2004;Zhang et al, 2005;Muller-Vieira et al, 2005;Hecker et al, 2006;Gracia et al, 2006;Oskarsson et al, 2006) with the consensus that it is a relevant, suitable and sensitive system for evaluating mechanisms of adrenocortical function. H295R cell systems can be used to assess the effects of compounds on steroid production and secretion (e.g.…”

Section: Identifying Molecular Targets and Mechanismsmentioning

confidence: 99%

“…H295R cell systems can be used to assess the effects of compounds on steroid production and secretion (e.g. Muller-Vieira et al, 2005;Imagawa et al, 2006;Oskarsson et al, 2006;Voets et al, 2004) on steroidogenic enzyme activity (e.g. Ohno et al, 2002;Canton et al, 2006;Oskarrson et al, 2006) and for gene expression profiling of key steroidogenic genes (e.g.…”

Section: Identifying Molecular Targets and Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

Harvey

Everett

Springall

2007

J of Applied Toxicology

View full text Add to dashboard Cite

The adrenal is the most common toxicological target organ in the endocrine system in vivo and yet it is neglected in regulatory endocrine disruption screening and testing. There has been a recent marked increase in interest in adrenal toxicity, but there are no standardised approaches for assessment. Consequently, a strategy is proposed to evaluate adrenocortical toxicity. Human adrenal conditions are reviewed and adrenocortical suppression, known to have been iatrogenically induced leading to Addisonian crisis and death, is identified as the toxicological hazard of most concern. The consequences of inhibition of key steroidogenic enzymes and the possible toxicological modulation of other adrenal conditions are also highlighted. The proposed strategy involves an in vivo rodent adrenal competency test based on ACTH challenge to specifically examine adrenocortical suppression. The H295R human adrenocortical carcinoma cell line is also proposed to identify molecular targets, and is useful for measuring steroids, enzymes or gene expression. Hypothalamo-pituitary-adrenal endocrinology relevant to rodent and human toxicology is reviewed (with an emphasis on multi-endocrine axis effects on the adrenal and also how the adrenal affects a variety of other hormones) and the endocrinology of the H295R cell line is also described. Chemicals known to induce adrenocortical toxicity are reviewed and over 60 examples of compounds and their confirmed steroidogenic targets are presented, with much of this work published very recently using H295R cell systems. In proposing a strategy for adrenocortical toxicity assessment, the outlined techniques will provide hazard assessment data but it will be regulatory agencies that must consider the significance of such data in risk extrapolation models. The cases of etomindate and aminoglutethimide induced adrenal suppression are clearly documented examples of iatrogenic adrenal toxicity in humans. Environmentally, sentinel species, such as fish, have also shown evidence of adrenal endocrine disruption attributed to exposure to chemicals. The extent of human sub-clinical adrenal effects from environmental chemical exposures is unknown, and the extent to which environmental chemicals may act as a contributory factor to human adrenal conditions following chronic low-level exposures will remain unknown unless purposefully studied.

show abstract

Section: Identifying Molecular Targets and Mechanismsmentioning

confidence: 99%

Section: Identifying Molecular Targets and Mechanismsmentioning

confidence: 99%

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

Harvey

Everett

Springall

2007

J of Applied Toxicology

View full text Add to dashboard Cite

show abstract

“…In the last decade great efforts were undertaken to develop lead structures from hits discovered by compound library screening [11][12][13][14]. Furthermore, a screening system was established to evaluate the potency and the selectivity of the compounds obtained by structural optimization [15][16][17]. Recently, we succeeded in developing aldosterone synthase inhibitors with improved activity and selectivity against other steroidogenic enzymes such as CYP11B1, CYP17 and CYP19 as well as hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo

Ries

Lucas

Heim

et al. 2009

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

“…FAD is the R-(ϩ)-enantiomer of the racemic CYP19 (aromatase) inhibitor CGS016949A (fadrozole), which is marketed in Japan as a treatment for estrogen-dependent breast cancer. Although its antipode is an aromatase inhibitor, FAD potently inhibits human AS in vitro (Fiebeler et al, 2005;Mü ller-Vieira et al, 2005;Mulder et al, 2008;LaSala et al, 2009). Its potency against AS from nonhuman species is unknown.…”

mentioning

confidence: 99%

Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone

Rigel

Fu²,

Beil³

et al. 2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Aldosterone synthase (CYP11B2) inhibitors (ASIs) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/ pharmacodynamic relationships of a prototypical ASI, (ϩ)-(5R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile hydrochloride (CGS020286A, FAD286, FAD) and compared these profiles to those of the 11␤-hydroxylase inhibitor metyrapone (MET) in two rodent models of secondary hyperaldosteronism and corticosteronism. In chronically cannulated Sprague-Dawley rats, angiotensin II (ANG II) (300 ng/kg bolus ϩ 100 ng/kg/ min infusion) or adrenocorticotropin (100 ng/kg ϩ 30 ng/kg/ min) acutely elevated plasma aldosterone concentration (PAC) from ϳ0.26 nM to a sustained level of ϳ2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ϳ300 to ϳ1340 nM. After 1 h of Ang II or adrenocorticotropin infusion, FAD (0.01-100 mg/kg p.o.) or MET (0.1-300 mg/kg p.o.) doseand drug plasma concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was ϳ12 times more dose-potent than MET in reducing PAC but of similar or slightly greater potency on a plasma drug concentration basis. Both agents also decreased PCC in the adrenocorticotropin model at relatively higher doses and with similar dose potencies, whereas FAD was 6-fold weaker based on drug exposures. FAD was ϳ50-fold selective for reducing PAC versus PCC, whereas MET was only ϳ3-fold selective. We conclude that FAD is a potent, orally active, and relatively selective ASI in two rat models of hyperaldosteronism. MET is an order of magnitude less selective than FAD but is, nevertheless, more potent as an ASI than as an 11␤-hydroxylase inhibitor.

show abstract

The adrenocortical tumor cell line NCI-H295R as an in vitro screening system for the evaluation of CYP11B2 (aldosterone synthase) and CYP11B1 (steroid-11β-hydroxylase) inhibitors

Cited by 32 publications

References 39 publications

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo

Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone

Contact Info

Product

Resources

About