Subchronic toxicity of all-trans-retinoic acid and retinylidene dimedone in Sprague-Dawley rats

Kurtz, P. J.; Emmerling, Donald C.; Donofrio, David J.

doi:10.1016/0300-483x(84)90122-7

Cited by 28 publications

(17 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The phenotype observed in the Cyp26a1 -/-b1 -/mice is very similar to the observed phenotype in mice and rats after chronic dosing with atRA. While acute atRA toxicity results in hair loss, dermal and mucosal alterations and loss of body weight (Kretzschmar and Leuschner, 1975;Biesalski, 1989), chronic atRA treatment has been shown to cause lymphoid hyperplasia, extramedullary hematopoiesis and hyperkeratosis (Kurtz et al, 1984), findings that are very similar to the phenotype observed in this study. The observations that exogenous atRA clearance was reduced in the Cyp26a1 -/-b1 -/mice by 80% and the Cyp26a1 -/-b1 -/mice were hypersensitive to atRA toxicity, further confirm the critical role of Cyp26a1 and Cyp26b1 in clearing atRA in post-natal animals.…”

Section: -Cis-rasupporting

confidence: 79%

“…Hypervitaminosis A cases have changes in central nervous system, liver disorders, changes to the bone and effects on skin and mucous membranes, but the exact mechanisms and the retinoids causing these toxicities cannot be easily delineated (Biesalski, 1989). Chronic (13-week) dosing of atRA to rats (14 or 50 mg/kg) caused lymphoid hyperplasia, splenic extramedullary hematopoiesis, hyperkeratosis of the non-glandular stomach, long-bone fractures, hematological changes and testicular degeneration and atrophy (Kurtz et al, 1984). After acute treatment the toxic doses are much higher (Kretzschmar and Leuschner, 1975;Biesalski, 1989).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

Snyder

Zhong

Hogarth

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractAll-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.

show abstract

Section: -Cis-rasupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

Snyder

Zhong

Hogarth

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Rats that were administered 14 mg/kg of all-trans-RA for 13 weeks showed signs of growth arrest, anemia, elevated serum alkaline phosphatase, bone fracture and testicular degeneration. 48 Microcephaly in particular is a recognized malformation of the central nervous system associated with hypervitaminosis A in early pregnancy. 49 Benke 50 described two infants with microcephaly, frontal bossing, hydrocephalus, microphthalmia and small, malformed and low-set undifferentiated ears whose mothers had taken the drug isotretinoin in the first trimester of pregnancy.…”

Section: Similarities To Hypervitaminosis Amentioning

confidence: 99%

Pathogenesis of Zika Virus-Associated Embryopathy

Mawson

2016

BioResearch Open Access

View full text Add to dashboard Cite

A strong causal association has become evident between Zika virus (ZIKV) infection during pregnancy and the occurrence of fetal growth restriction, microcephaly and eye defects. Circumstantial evidence is presented in this paper in support of the hypothesis that these effects, as well as the Guillain-Barré syndrome, are due to an endogenous form of hypervitaminosis A resulting from ZIKV infection-induced damage to the liver and the spillage of stored vitamin A compounds (“retinoids”) into the maternal and fetal circulation in toxic concentrations. Retinoids are mainly stored in the liver (about 80%) and are essential for numerous biological functions. In higher concentration, retinoids are potentially cytotoxic, pro-oxidant, mutagenic and teratogenic, especially if sudden shifts occur in their bodily distribution. Although liver involvement has not been mentioned specifically in recent reports, conventional liver enzyme tests underestimate the true extent of liver dysfunction. The proposed model could be tested by comparing retinoid concentration and expression profiles in microcephalic newborns of ZIKV-infected mothers and nonmicrocephalic newborn controls, and by correlating these profiles with measures of clinical severity.

show abstract

“…[Windhorst and Nigra 1982;Frankel et al, 1992Frankel et al, , 1994. Subchronic toxicity including alterations in body weight gain, bone resorption, RBC count, hemoglobin, hematocrit, cholesterol, serum albumin, and alkaline phosphatase in mice and rats have been described [Hixson and Denine 1978;Hixson et al, 1979;Teelman 1983;Kurtz et al, 1984]. The main toxicities observed in the present study were consistent with the previous reports mentioned above, and severe toxic effects were observed after continuous plasma exposure to atRA over 10 ng/ml for more than 1 week, and, therefore, it could be suggested that the minimum toxic concentration of atRA was around 10 ng/ml of plasma.…”

Section: Discussionmentioning

confidence: 99%

Subacute toxicity of all‐trans‐retinoic acid loaded biodegradable microspheres in rats

Choi¹,

Lee²,

Park³

et al. 2003

Drug Development Research

View full text Add to dashboard Cite

Biodegradable microspheres containing all-trans-retinoic acid (atRA) were prepared previously to enhance the clinical efficacy of atRA for chemoprevention. In this study, subacute toxicity of atRA in sustained release was evaluated after subcutaneous administration of 0, 25, 50, and 100 mg atRA/ kg of atRA-loaded microspheres. After the subcutaneous injection of atRA-loaded microspheres, the atRA concentration in plasma was maintained in the range of 3.5-25 ng/ml for 2-3 weeks. When 100 mg atRA/kg was administered, the atRA concentration in plasma was maintained at levels greater than 10 ng/ ml and severe toxic effects were observed. When the dose of 50 mg atRA/kg was administered, the plasma concentration of atRA was maintained below 10 ng/ml over 3 weeks and only mild signs of toxicity were observed. Therefore, it was concluded that the dosage of atRA-loaded microspheres should be less than 50 mg atRA/kg for chemopreventive applications against carcinogenesis. Considering recovery from intoxication, the optimum interval for repeated injection of the microspheres was suggested to be over 4 weeks. In addition, it was found that the atRA concentration in plasma should be controlled below 10 ng/ml to minimize toxic effects of atRA. Drug Dev. Res. 59:326-332, 2003.

show abstract

Subchronic toxicity of all-trans-retinoic acid and retinylidene dimedone in Sprague-Dawley rats

Cited by 28 publications

References 6 publications

Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

Pathogenesis of Zika Virus-Associated Embryopathy

Subacute toxicity of all‐trans‐retinoic acid loaded biodegradable microspheres in rats

Contact Info

Product

Resources

About