Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: Induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers

Saito, Koichi; Kaneko, Hideo; Satô, Keiko; Yoshitake, Akira; Yamada, Hirohiko

doi:10.1016/0041-008x(91)90138-5

Cited by 73 publications

(36 citation statements)

References 24 publications

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“…The increase in the liver weight associated with microsomal enzyme induction and subsequent thyroidal chang--vious works; these changes have been well documented as the typical effects of PB (Goldsworthy et al, 1984;Kitagawa et al, 1984;Maekawa et al, 1992;Hagiwara et al, 1996;McClain et al, 1989;Saito et al, 1991;Hood and Klaassen, 2000). It has been shown that PB enhances cell proliferation in the liver and subsequently in the then returns to normal levels thereafter (Jones and Clarke, 1993;Kolaja et al, 1996;Hood et al, 1999).…”

Section: Other Toxicitiesmentioning

confidence: 99%

“…Dosing volumes were calculated at 5 ml/kg of body weight measured on the latest day of administration. The doses were selected on the basis of the results of previous studies with PB in rats (Goldsworthy et al, 1984;McClain et al, 1989;Saito et al, 1991;Jones and Clarke, 1993). These animals were housed individually in suspended stainless steel cages in an air-conditioned animal room with a temperature of 20-24°C, humidity of 30-70%, ventilation of 10 times or more per hr (all-fresh-air basis), and illumination for 12 hr/day (light, 07:00 to 19:00).…”

Section: Animals and Experimental Designmentioning

confidence: 99%

“…PB has been widely used to induce microsomal enzymes and promote rat liver carcinogenesis (Goldsworthy et al, 1984;Kitagawa et al, 1984;Maekawa et al, 1992;Jones and Clarke, 1993;Hagiwara et al, 1996;Kolaja et al, 1996). The inducible hepatic enzyme UDP-glucuronyltransferase has adverse effects on thyroid hormone metabolism: it reduces circulating thyroid hormones and subsequently enhances thyroid stimulating hormone, leading to adaptive hyperthyroidism (McClain et al, 1989;Saito et al, 1991;Hood et al, 1999;Hood and Klaassen, 2000). However, the general toxicity of PB, including hematological and blood biochemical alterations, has not yet been fully elucidated (Noguchi et al, 1994;Rana and Gupta, 1999).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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-A 4-week repeated dose oral toxicity study of phenobarbital (PB) sodium was conducted in F344 rats of both sexes at PB doses of 0.8, 8, and 80 mg/kg/day to fully elucidate its general toxicity including hematological changes. Both sexes in the 80 mg/kg/day group showed staggering gait, lacrimation, and/or sedation, which were more evident in the early stage of treatment. The body weight gain reduction in the hematocrit (Ht), hemoglobin concentration (Hb), and erythrocyte count (RBC) in both sexes at 80 mg/kg/day, which was accompanied by a decrease in the cell mean Hb (CHCM) in mature erythrocytes with an increase in unsaturated iron binding capacity. Female rats also showed reduction in the CHCM in reticulocytes, content of hemoglobin per reticulocyte, and transferrin saturation. PB prolonged the activated partial thromboplastin time and inversely increased the platelet count with no evidence of platelet activation. Well-known toxic effects of PB on the liver and thyroid were observed in a dose-dependent manner, along with altered lipid, glucose, and electrolyte metabolism. The serum levels of PB increased dose-dependently, when examined in females received 8 and 80 mg/kg/day on day 1 and 28; there were no difference in C max and AUC 0-24 values between day 1 and day 28. These results indicated that PB has the potential to elicit multiple organ toxicity including an effect on the hematopoietic system. The hematological analysis provided evidence for hypochromic anemia, plausibly caused by the impairment of iron utility.

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Section: Other Toxicitiesmentioning

confidence: 99%

Section: Animals and Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…These findings have been replicated in numerous comparable studies in Sprague Dawley rats (Barter and Klaassen 1994;Capen 1997;Hood et al 2003, Hood, Hashimi et al 1999Hood, Liu et al 1999;McClain et al 1989). Development of thyroid follicular hypertrophy, hyperplasia, and progression to neoplasia occured with chronic PB administration in rats (Capen 1997;McClain et al 1989;Meek et al 2003); however, similar patterns of thyroid hormone changes without thyroid tumorigenesis were seen in rats given other microsomal enzyme inducing compounds including 3-methylcholanthrene and pregnenolone-16-a-carbonitrile (Barter and Klaassen 1994;De Sandro et al 1992;Saito et al 1991).…”

Section: Effects Of Enzyme Induction On Endogenous Thyroid Hormones Imentioning

confidence: 99%

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

et al. 2010

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Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.

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“…Such treatment results in increased serum TSH levels and in concomitant hypertrophy of thyroid follicular cells and thyroid hyperplasia (115). Other Ah agonists have similar effects as dioxin (116,117). Goitro A threshold for a response to a carcinogen has been defined in absolute biological terms as the dose below which no response occurs.…”

Section: Inducers Of X2-microglobulin Nephropathy and Kidy Cancer In mentioning

confidence: 99%

Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

Melnick

Kohn

Portier

1996

Environ Health Perspect

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Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: Induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers

Cited by 73 publications

References 24 publications

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

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

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

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