Multiple organ toxicity, including hypochromic anemia, following repeated dose oral administration of phenobarbital (PB) in rats

Kojima, Sayuri; Sasaki, Junya; Tomita, Mariko; Saka, Machiko; Ishizuka, Katsumi; Kawakatsu, Hisao; Yoshida, Toshinori; Kosaka, Toshio; Enomoto, Akiko; Nakashima, Nobuaki; Harada, Takanori

doi:10.2131/jts.34.527

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…CHr measurement is a direct assessment of the incorporation of Fe into erythrocyte haemoglobin, and it is free from the biological variability that affects Fe, transferrin measurements, and transferrin saturation (Goodnough et al, 2000;Thomas and Thomas, 2002;Ullrich et al, 2005). Our data suggests that CHCM and CHr are critical parameters for characterizing anaemia, and this is supported by our previous study (Kojima et al, 2009) and other study (Honda et al, 2008). Classically, MTX efficacy depends on its inhibition of DHFR, resulting in depletion of intracellular reduced folates that are crucial for biosynthesis of purines and thymidilic acid, the precursors of DNA (Jolivet et al, 1983;Schornagel and McVie, 1983;Blakley, 1995).…”

Section: Discussionsupporting

confidence: 85%

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

et al. 2012

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-Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.

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Section: Discussionsupporting

confidence: 85%

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

et al. 2012

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“…2004), and through the PB/PB receptor‐GABA receptor‐chloride channel complex leads to hyperphagia. Therefore, as shown in our data, we confirm again that phenobarbital would induce weight gain in female rats (Cooper and Moores 1985; Kojima et al . 2009).…”

Section: Discussionsupporting

confidence: 91%

“…For another, similar to the benzodiazepine, PB direct or indirect stimulates the gammaaminobutyric acid (GABA) receptor (Roberge et al 2004), and through the PB/PB receptor-GABA receptor-chloride channel complex leads to hyperphagia. Therefore, as shown in our data, we confirm again that phenobarbital would induce weight gain in female rats (Cooper and Moores 1985;Kojima et al 2009).…”

Section: Discussionsupporting

confidence: 90%

Hypothyroidism caused by phenobarbital affects patterns of estrous cyclicity in rats

Kumazawa

Ishiguro

et al. 2011

Congenital Anomalies

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We found that repeated treatment with phenobarbital (PB), a thyroid modulator, resulted in a persistent estrous stage in the present study. Although the effects of PB in blocking the surge release of luteinizing hormone (LH), inducing anovulation and prolonging the diestrous period has been well established, there is still no research describing the appearance of persistent estrous states in normal cycling rats dosed with PB. To further study this phenomenon, female rats exhibiting regular estrous cycle were administered an oral dose of PB for 14 consecutive days. Consecutively, vaginal smears were observed and rats from all the groups were sacrificed and serum hormone levels for prolactin, progesterone, estradiol, triiodothyronin (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were measured. Pituitary, thyroid, liver, uteri and ovaries were excised, weighed and further subjected to histological observations. We found that PB induced irregular estrous cycles, especially persistent estrus in rats. Histopathologically, the persistent estrous stages are characterized by persistent vaginal cornification in the vagina, cystic follicles and anovulation in the ovaries. Endocrinologically, serum T3 and T4 levels were significantly lower, and TSH was higher in treated-female rats compared to control females. The serum estradiol level and the estradiol/progesterone ratio tend to increase in treated-females. Furthermore, PB-treated animals with irregular estrous cycle were reduced by T4 replacement. Our data indicate that treatment with PB resulted in hypothyroidism and irregular estrous cycle, particularly a persistent estrous stage in normal cycling female rats.

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“…It has been known that LPS treatment increases T.Chol via an increase of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (Feingold et al, 1993), as well as the suppressed conversion of cholesterol to bile acids via decreases in 7 alpha-hydroxylase (Feingold et al, 1996) and sterol 27-hydroxylase (Memon et al, 2001). Although the effect of p,p -DDT on lipid metabolism has, to our knowledge, not been investigated, an elevation in serum cholesterol has been demonstrated by treatment with the hepatic drug-metabolizing enzyme inducer (HDMEI) phenobarbital (PB) (Kojima et al, 2009). PB treatment was clearly accompanied by a decrease in HMGCoA synthetase, which is a rate-limiting enzyme for ketogenesis, and by increases in oxidosqualene lanosterol-cyclase and 3␣-hydroxysteroid dehydrogenase, both of which are cholesterogenic enzymes (Kiyosawa et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lipopolysaccharide-induced liver injury in rats treated with a hepatic drug-metabolizing enzyme inducer p,p′-DDT

Shimada¹,

Tomita²,

Yoshida³

et al. 2015

Experimental and Toxicologic Pathology

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Multiple organ toxicity, including hypochromic anemia, following repeated dose oral administration of phenobarbital (PB) in rats

Cited by 10 publications

References 46 publications

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Hypothyroidism caused by phenobarbital affects patterns of estrous cyclicity in rats

Inhibition of lipopolysaccharide-induced liver injury in rats treated with a hepatic drug-metabolizing enzyme inducer p,p′-DDT

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