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The effects of PKC (Protein Kinase C) inhibitors on steroid hormones: a 2-week rat oral (gavage) investigative study focusing on pathology and hormone analysis in plasma and tissues

Dincer, Zuhal and Schadt, Heiko and Junker Walker, Ursula and Piaia, Alessandro and Pognan, Francois and Cordier, Andre and Spence, Fiona and Chibout, Salah-Dine (2013) The effects of PKC (Protein Kinase C) inhibitors on steroid hormones: a 2-week rat oral (gavage) investigative study focusing on pathology and hormone analysis in plasma and tissues. ESTP 2013 Congress.

Abstract

The Protein Kinase C (PKC) family is a family of serine/threonine kinases with various classical and novel isoforms. Some of these isoforms are expressed in T and B cells and have a key role in T-lymphocyte activation, downstream of the T-cell receptor and CD28 co-receptor signaling, therefore being used as immunosuppressive agents. PKC could also have a potential role as a receptor and/or transducer of the non-genomic effects of steroid hormones which regulate a wide variety of cellular responses (regulation of ion transport and cell proliferation/migration/differentiation and death) (Alzamora and Harvey, 2008). The inhibition of PKC could alter steroid hormone actions and regulation leading to disturbances in multiple organ systems, particularly the reproductive system.

To investigate the potential effects of PKC inhibitors on steroid hormones and its consequences, a 2-week oral mechanistic study in rats was conducted with a PKC inhibitor at two doses, focusing on pathology and hormone analysis in plasma and tissues. In males, tubuloalveolar pattern (feminization) in the mammary glands was observed microscopically and hormone analysis showed decreased androstenedione and testosterone concentrations in plasma, adrenals and testes. In females, atretic follicles and corpora luteal degeneration in ovaries was present microscopically, accompanied with disturbed estrus cycle, as evident in the vagina histology and vaginal smear cytology. Hormone analysis revealed decreased estrogens and its precursor androstenedione in the ovaries. Progesterone was increased in ovarian and adrenal tissues, whereas it was decreased in plasma. In both sexes, Luteinizing Hormone (LH) was decreased in blood. LH decrease was considered responsible for the reduction of androgens, estrogens and plasma progesterone which in turn led to the observed disturbances in estrous cycle. However, as progesterone levels were elevated in ovaries, it was thought that PKC inhibitor might have an additional direct effect in the corpora lutea which is independent of the LH reduction. In both sexes, aldosterone was elevated in plasma and adrenal glands associated with increased cortical vacuolation microscopically.

Lymphoid depletion of various lymphoid organs (thymus, lymph nodes and spleen) seen in both sexes at both doses was consistent with known immunosuppressive effects of PKC inhibitors. Absent/decreased germinal centers of lymph nodes are also supportive of the inhibitory properties on lymphocyte activation and proliferation by PKC inhibitors (Matz et al, 2011).

In summary, the results of this study support possible PKC inhibitors induced hormonal imbalances in the rat, likely due to a disturbance of the hypothalamus-pituitary-gonad axis and/or direct effect on the ovaries and adrenals. The results also confirm the expected immunosuppressive effect of PKC inhibitors.

References:
Alzamora and Harvey (2008). Direct binding and activation of protein kinase C isoforms by steroid hormones. Steroids 73 (9-10), 885-888.

Matz et al (2011). Evaluation of the novel protein kinase C inhibitors otrastaurin as immunosuppressive therapy after renal transplantation. Expert Opin Drug Metab Toxicol, 7 (1): 103-113.

Item Type: Article
Keywords: Protein Kinase C inhibitor
Date Deposited: 30 Apr 2016 23:45
Last Modified: 30 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/10746

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