Comparative Effects of Ketoconazole on Rat, Dog and Human Testicular Steroidogenesis

Coster, R. De; Coene, M.‐C.; Camp, C. van; Camp, K. Van; Beerens, D.; Cools, W.

doi:10.3109/14756368909088479

Cited by 14 publications

(9 citation statements)

References 24 publications

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“…These compounds inhibit testosterone biosynthesis because the testosterone pathway contains three P 450 isozymes: C 27 -side chain cleavage, C 17a -hydroxylase, and C 17, 20 -lyase enzymes. For instance, ketoconazole has been shown to differentially inhibit these three isozymes where sensitivity from most sensitive to least sensitive appears to be C 17, 20 -lyase, C 17a -hydroxylase, and C 27 -side chain cleavage (De Coster et al, 1989;Morita et al, 1990;Kan et al, 1985;Sikka et al, 1985). Using isolated rat LCs, the inhibition of testosterone biosynthesis by ketoconazole has been shown to be reversible in in vitro (Kan et al, 1985) and ex vivo (Pont et al, 1982) studies.…”

Section: Testosterone Biosynthesis Inhibitorsmentioning

confidence: 95%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

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Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several ...

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Section: Testosterone Biosynthesis Inhibitorsmentioning

confidence: 95%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

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“…The relationship between azole derivativeinduced malformations and effects on metabolism of endogenous retinoic acid due to inhibition of CYP26 is thus convincing. On the other hand, azole derivatives have been shown to inhibit broad classes of mammalian CYPs other than CYP26 and CYP51, such as CYP11A, CYP11B, CYP17, CYP19, and CYP21, which mainly involve steroidogenesis including androgens and estrogens (Santen et al, 1983;Sikka et al, 1985;Pont et al, 1982;Loose et al, 1983;Kan et al, 1985;De Coster et al, 1989;Cummings et al, 1997). Since some KCZ-induced malformations clearly differed in shape and sensitive window from those of VAP-induced malformations, the mechanisms involved might include changes other than disorders of endogenous retinoic acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Since several reports have indicated that azole derivativeinduced malformations were associated with CYP 26 inhibition as well as inhibition of other CYPs related to the synthesis of glucocorticoids and sexual hormones (Santen et al, 1983;Sikka et al, 1985;Pont et al, 1982;Loose et al, 1983;De Coster et al, 1989;Cummings et al, 1997;Taxvig et al, 2008), two or more of these mechanisms are likely also to be involved in the teratogenic effects of KCZ in rats.…”

Section: Discussionmentioning

confidence: 99%

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum

Mineshima

Fukuta

Kato

et al. 2011

J of Applied Toxicology

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Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high-dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8-15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg(-1) ). Embryonic lethality was observed in dams given KCZ on GDs 9-12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ-induced malformation are related to excessive vitamin A.

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“…Much of what is currently known about the use of CYP17 inhibitors in clinical practice for PC treatment is related to ketocona- zole (2), an orally administered imidazole antifungal agent that was first reported to cause gynecomastia in male patients [25,32] and later found to inhibit rat [161][162][163][164], dog [164], and human CYP17 [25,26,165]. Although the mechanism by which ketoconazole (2) induces gynecomastia remains to be determined, it has been suggested that the suppression of testicular androgen production and concomitant displacement of estrogens from steroid hormone binding globulin (SHBG) that it causes would contribute to perturbations in the ratio of blood androgen/estrogen, thus satisfying one of the major criteria for the development of this condition [166].…”

Section: Imidazole Derivativesmentioning

confidence: 99%

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

Moreira

Salvador²,

Vasaitis³

et al. 2008

CMC

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It is almost 70 years since the discovery by Huggins et al. that androgens are essential for prostate cancer (PC) growth and progression, and there has been about 30 years experience using ketoconazole for PC therapy. Since then we have come a long way in learning about the disease and developing new strategies to approach it, among which is cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17) inhibition. This review focuses on the efforts to find prospective CYP17 inhibitors, both steroidal and nonsteroidal, in the absence of a 3D structure of the enzyme. It covers almost 4 decades of literature with highlights on the most significant achievements in this area, providing insight into PC pathophysiology, management and treatment options.

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Comparative Effects of Ketoconazole on Rat, Dog and Human Testicular Steroidogenesis

Cited by 14 publications

References 24 publications

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

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