The Effects of &lt;I&gt;o,p&lt;/I&gt;′-DDD on Adrenal Steroidogenesis and Hepatic Steroid Metabolism

Ojima, Motoko; Saitoh, Manichiro; Itoh, Nobuo; Kusano, Yoshiro; Fukuchi, Soitsu; Naganuma, Hiroshi

doi:10.1507/endocrine1927.61.3_168

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…Our interpretation that mitotane probably specifically inhibits 5ARD2 assumes that decrease in the ratio of 5α/5β-reduced metabolites reflects only decrease in 5α-reductase activity, but both mitotane (28) and finasteride (29) also inhibit 5β-reductase (AKR1D1); we could not locate any reports of an effect of dutasteride. This could contribute to the smaller change in these ratios during mitotane and finasteride than during dutasteride.…”

Section: Discussionmentioning

confidence: 58%

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Ghataore¹,

Chakraborti²,

Aylwin³

et al. 2012

Endocrine Connections

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Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6β-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography–mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14–20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6β-hydroxycortisol and 6β-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35–52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5β- and 20β-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females – mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5β-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6β-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20β-reduction.

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Section: Discussionmentioning

confidence: 58%

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Ghataore¹,

Chakraborti²,

Aylwin³

et al. 2012

Endocrine Connections

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“…( Figure 5(f) ). DDD has been reported to inhibit CYP11A1, HSD3B2, CYP21A2, CYP11B1, and CYP11B2 [ 29 , 31 , 32 ]. Inhibition of DDD by CYP11B2 was not estimated in our study.…”

Section: Resultsmentioning

confidence: 99%

“…However, the concentration of ALDO in the culture medium decreased to 3% of that in the normal stimulated condition. Inhibition of DDD by CYP11B2 has been shown using mitochondrial and microsomal fractions prepared by standard centrifugation procedures from a bovine adrenal cortex homogenate [ 32 ]. The cause of the discrepancy regarding the inhibition of DDD by CYP11B2 could not be explained by same effect in the case of AGT.…”

Section: Resultsmentioning

confidence: 99%

Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells

Saito

Terasaki²,

Yamazaki³

et al. 2016

Journal of Toxicology

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Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

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“…Mitotane inhibits side-chain cleavage of cholesterol, 1 1-hydroxylase and 1 8-hydroxylase activity, and 3p-hydroxysteroid dehydrogenase activity (7,8). Due to its adrenolytic proper-ties, mitotane has been used in patients with metastatic adrenocortical cancer.…”

Section: Discussionmentioning

confidence: 99%

Adrenocorticotropic Hormone-Independent Bilateral Adrenocortical Macronodular Hyperplasia Treated with Mitotane.

et al. 1999

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Wereport a case of adrenocorticotropic hormone (ACTH)-independent bilateral macronodular adrenocortical hyperplasia (AIMAH), which was successfully treated with mitotane.A 71-year-old man visited our hospital because of central obesity and enlarged bilateral adrenal glands. The endocrinological studies showed elevated plasma cortisol and undetectable levels of ACTH,a lack of suppression with high-dose dexamethasone and a hyper-response to exogenous ACTH. These clinical features were compatible with the diagnosis of AIMAH. In this patient, extra-adrenal multiple tumors were also detected. After treatment with mitotane, the plasma level of cortisol was decreased while that of ACTHwas increased and the signs of Cushing's syndrome were resolved. (Internal Medicine 38: 969-973, 1999)

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The Effects of <I>o,p</I>′-DDD on Adrenal Steroidogenesis and Hepatic Steroid Metabolism

Cited by 8 publications

References 11 publications

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells

Adrenocorticotropic Hormone-Independent Bilateral Adrenocortical Macronodular Hyperplasia Treated with Mitotane.

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