Comparative teratogenicity of three retinoids: The arotinoids Ro 13-7410, Ro 13-6298 and Ro 15-1570

Kistler, Andreas D.; Galli, Brigitta; Wb, Howard

doi:10.1007/bf01973375

Cited by 18 publications

(8 citation statements)

References 20 publications

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“…To corroborate the hypothesis that Liarozole inhibited regeneration due to increased RA signaling that results from the raising of endogenous RA levels, we also treated eyes with TTNPB and all-trans RA, and saw the same effect. TTNPB has been documented as a significantly more potent retinoid than all-trans RA, and is resistant to metabolism by CYP26 (Kistler et al, 1990; Pignatello et al, 1997, 1999). Although TTNPB effectively inhibited lens regeneration, we did not observe a significantly greater inhibition of regeneration with the use of TTNPB compared to all-trans RA.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid regulation by CYP26 in vertebrate lens regeneration

Thomas

Henry

2014

Developmental Biology

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Xenopus laevis is among the few species that are capable of fully regenerating a lost lens de novo. This occurs upon removal of the lens, when secreted factors from the retina are permitted to reach the cornea epithelium and trigger it to form a new lens. Although many studies have investigated the retinal factors that initiate lens regeneration, relatively little is known about what factors support this process and make the cornea competent to form a lens. We presently investigate the role of Retinoic acid (RA) signaling in lens regeneration in Xenopus. RA is a highly important morphogen during vertebrate development, including the development of various eye tissues, and has been previously implicated in several regenerative processes as well. For instance, Wolffian lens regeneration in the newt requires active RA signaling. In contrast, we provide evidence here that lens regeneration in Xenopus actually depends on the attenuation of RA signaling, which is regulated by the RA-degrading enzyme CYP26. Using RTPCR we examined the expression of RA synthesis and metabolism related genes within ocular tissues. We found expression of aldh1a1, aldh1a2, and aldh1a3, as well as cyp26a1 and cyp26b1 in both normal and regenerating corneal tissue. On the other hand, cyp26c1 does not appear to be expressed in either control or regenerating corneas, but it is expressed in the lens. Additionally in the lens, we found expression of aldh1a1 and aldh1a2, but not aldh1a3. Using an inhibitor of CYP26, and separately using exogenous retinoids, as well as RA signaling inhibitors, we demonstrate that CYP26 activity is necessary for lens regeneration to occur. We also find using phosphorylated Histone H3 labeling that CYP26 antagonism reduces cell proliferation in the cornea, and using qPCR we find that exogenous retinoids alter the expression of putative corneal stem cell markers. Furthermore, the Xenopus cornea is composed of an outer layer and inner basal epithelium, as well as a deeper fibrillar layer sparsely populated with cells. We employed antibody staining to visualize the localization of CYP26A, CYP26B, and RALDH1 within these corneal layers. Immunohistochemical staining of these enzymes revealed that all 3 proteins are expressed in both the outer and basal layers. CYP26A appears to be unique in also being present in the deeper fibrillar layer, which may contain cornea stem cells. This study reveals a clear molecular difference between newt and Xenopus lens regeneration, and it implicates CYP26 in the latter regenerative process.

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Section: Discussionmentioning

confidence: 99%

Retinoic acid regulation by CYP26 in vertebrate lens regeneration

Thomas

Henry

2014

Developmental Biology

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“…In general, the teratogenic potency of a retinoid correlates with its conversion potential to atRA, increasing half‐life/maternal clearance, and its ability to traverse the placenta (Soprano and Soprano,1995; Nau,2001). Teratogenic retinoids must be able to bind RAR, but strength of binding does not correlate well with teratogenic potency (arotinoids are much more potent teratogens than atRA but bind RAR approximately equivalently) (Kistler et al,1990; Bechter et al,1992; Nau,2001). Whereas developing retinoids that have therapeutic value without teratogenicity is problematic, since they would have to bind and activate the RAR, it may be possible to generate retinoids that are unable to be efficiently transferred to the embryo.…”

Section: Associations Of Cyp26 Mutations With Human Congenital Malformentioning

confidence: 99%

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

Pennimpede

Cameron

MacLean

et al. 2010

Birth Defects Research

125

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Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis.

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“…In addition, RAR antagonists may be useful in treating dermatologic and inflammatory diseases because of the pronounced influence of retinoid-receptor stimulation on collagen synthesis and IL-8 production (Bollag, 1985;Olsen et al, 1990;Vincenti et al, 1994;Wang and Guda, 1988). Although a large body of information exists regarding the toxicity of retinoid agonists (Hixson et al, 1979;Kamm, 1982;Kistler et al, 1990;Kurtz et al, 1984;Lindamood et al, 1987Lindamood et al, , 1990, the toxicity of retinoid antagonists utilizing in vivo experimental models has not been extensively studied. Therefore, studies were performed to investigate the potential target-organ toxicity of BMS-189453 in rats following 1 month of oral administration.…”

mentioning

confidence: 99%

BMS-189453, a Novel Retinoid Receptor Antagonist, Is a Potent Testicular Toxin

Schulze

Clay

Mezza

et al. 2001

Toxicological Sciences

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BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.

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Comparative teratogenicity of three retinoids: The arotinoids Ro 13-7410, Ro 13-6298 and Ro 15-1570

Cited by 18 publications

References 20 publications

Retinoic acid regulation by CYP26 in vertebrate lens regeneration

Retinoic acid regulation by CYP26 in vertebrate lens regeneration

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

BMS-189453, a Novel Retinoid Receptor Antagonist, Is a Potent Testicular Toxin

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