Reduction of thyroid hormone may participate in the modulation of cytochromes P450 2C11 and 3A2 by retinol

Badger, Drew A.; Kraner, James C.; Fraser, David; Hoglen, Niel C.; Halpert, James R.; Sipes, I. G.

doi:10.1016/s0024-3205(98)00516-5

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…We even found that Hypo+Doxo mice have higher levels of CYP enzymes in the liver than Eu+Doxo, which would also point to higher circulating levels of the active metabolite, thus contributing to the low tumor volume found in response to Doxo in hypothyroid mice. In support to our results it has been shown that Doxo decreases the hepatic expression of CYP enzymes in rats [47] and that THs can decrease CYP levels in human hepatocytes in vitro [48], so it would be expected that low circulating levels of them may increase hepatic CYP. Moreover, the effect of thyroid function on the efficacy of cancer therapies has been described and hypothyroidism was suggested to have a positive impact on treatment outcome [45, 49, 50].…”

Section: Discussionsupporting

confidence: 90%

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

et al. 2019

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Thyroid hormones (THs) – 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) – are important regulators of the metabolism and physiology of most normal tissues. Cytochrome P450 family 3A members are drug metabolizing enzymes involved in the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvβ3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo . In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.

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Section: Discussionsupporting

confidence: 90%

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

et al. 2019

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“…Hypothyroidism, a condition of thyroid hormone deficiency is quite prevalent, affecting about 1~2% of the general population. Among a number effects of hypothyroidism, animal data have shown that thyroid dysfunction can alter the expression of various drug-metabolizing enzymes, such as cytochrome P450s (CYPs), sulfotransferases, and uridine 5'-diphosphate-glucuronosyltransferases (Rosenberg et al ., 1995; Webb et al ., 1996; Badger et al ., 1998; Liddle et al ., 1998). CYPs are rate-limiting for drug metabolism and their induction accelerates metabolic clearance of a drug or its metabolites, while decreased CYP activity can lead to elevated accumulation of the xenobiotics, with potentially harmful effects.…”

Section: Introductionmentioning

confidence: 99%

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

Park

Lee

et al. 2012

Toxicology and Applied Pharmacology

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Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR-/- mice, but not in hypothyroid PXR-/- mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR-/- hypothyroid mice, and this induction was abolished in CAR-/- mice and in and CAR-/- PXR-/- double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR-/- mice and lowest in WT and PXR-/- mice. Hypothyroid WT or PXR-/- mice survived chronic CBZ treatment, but all hypothyroid CAR-/- and CAR-/- PXR-/- mice died, with CAR-/-PXR-/- mice surviving longer than CAR-/- mice (12.3 ±3.3 days vs. 6.3 ±2.1 days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.

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“…Students had a choice to run assays for either CYP3A or CYP2E1 in laboratory sessions 3 and 5. Due to the involvement of both isoforms in the metabolism of acetaminophen to NAPQI [21] students who understood the literature (Table I), would know that previous papers indicated that retinol can alter both CYP2E1 and CYP3A activity in rats [22–25]. Students had a choice of the following samples: untreated, retinol, acetaminophen/retinol, dexamethasone, or CCl 4 .…”

Section: Laboratory Sessionsmentioning

confidence: 99%

A laboratory course for teaching laboratory techniques, experimental design, statistical analysis, and peer review process to undergraduate science students

Gliddon¹,

Rosengren²

2012

Biochem Molecular Bio Educ

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This article describes a 13-week laboratory course called Human Toxicology taught at the University of Otago, New Zealand. This course used a guided inquiry based laboratory coupled with formative assessment and collaborative learning to develop in undergraduate students the skills of problem solving/critical thinking, data interpretation and written discussion of results. The laboratory practices were a guided inquiry based around retinol's ability to potentiate acetaminophen-mediated hepatotoxicity. To induce critical thinking, students were given a choice as to which assay they could use to determine how retinol affected acetaminophen hepatotoxicity. Short summaries were handed in following each assay and formed the bases of the formative assessment. To complete the feedback loop, a summative assessment that consisted of all the graphs and concepts from the short summaries were combined into a manuscript. To give the students exposure to science communication, the manuscript had to be written in accordance to the submission guidelines for Toxicological Sciences. Evaluation of this course was determined by a student questionnaire using a Likert scale and students' responses were very favorable. While the subject matter was toxicological centric, the content could be easily modified to suit another subject matter in biochemistry and molecular biology.

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Reduction of thyroid hormone may participate in the modulation of cytochromes P450 2C11 and 3A2 by retinol

Cited by 10 publications

References 11 publications

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

A laboratory course for teaching laboratory techniques, experimental design, statistical analysis, and peer review process to undergraduate science students

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