Thyroid hormone suppression of hepatic levels of phenobarbital-inducible P-450b AND P-450e and other neonatal P-450S in hypophysectomized rats

doi:10.1016/0006-291X(89)92476-5

Biochemical and Biophysical Research Communications

Volume 160, Issue 2, 28 April 1989, Pages 609-614

https://doi.org/10.1016/0006-291X(89)92476-5 Get rights and content

Abstract

Mechanism of developmental suppression of cytochrome P-450 (P-450) in rat livers was studied using Western blots. The contents of phenobarbital (PB)-inducible P-450b and P-450e, expressed constitutively in livers, were higher in neonate than in adult rats. The contents were also 10∼50 fold higher in hypophysectomized than in intact adult male rats. Administration of L-triiodothyronine (T₃, 50 μg/kg) or human growth hormone (4U/kg) reversed almost completely the increased amounts of P-450b and P-450e. T₃-induced suppression was also observed on two other neonatal P-450s (P-450_6β-1 and P-448-H), which are expressed in neonatal periods in livers. The postnatal developmental profiles of hepatic P-450b were correlated inversely with that of serum free T₃ level in rats reported (Walkeret al. (1980) Pediat. Res. 14, 249). These results suggest, in addition to pituitary growth hormone (Yamazoeet al. (1987) J. Biol. Chem. 262, 7423), the possible involvement of T₃ on the suppressive regulation of PB-inducible and other neonatal P-450s.

References (28)

KamatakiT. et al.
Arch. Biochem. Biophys.
(1983)
KamatakiT. et al.
Biochem. Biophys. Res. Commun.
(1985)
YamazoeY. et al.
Jpn. J. Pharmacol.
(1986)
MorganE.T. et al.
J. Biol. Chem.
(1985)
DannanG.A. et al.
J. Biol. Chem.
(1986)
YamazoeY. et al.
Arch. Biochem. Biophys.
(1989)
BandieraS. et al.
Arch. Biochem. Biophys.
(1986)
YamazoeY. et al.
J. Biol. Chem.
(1987)
RyanD.E. et al.
Arch. Biochem. Biophys.
(1984)
FlugF. et al.
J. Biol. Chem.
(1987)

KatoR. et al.

Biochim. Biophys. Acta

(1970)

KatoR. et al.

Biochem. Pharmacol.

(1971)

HochF.L.

Prog. Lipid Res.

(1988)

YamazoeY. et al.

J. Biochem.

(1986)

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Activation of brain serotonergic system by repeated intracerebral administration of 5-hydroxytryptophan (5-HTP) decreases the expression and activity of liver cytochrome P450
2016, Biochemical Pharmacology
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It has been shown that the level of CYP2C11 expression in male rats correlates positively with the serum concentration of GH [20]. On the other hand, thyroid hormones and the investigated interleukins exert negative influence on the activity of the CYP isoforms studied [25,31⿿34]. Therefore we assume that the changes observed in serum hormone concentrations, i.e. a decrease in GH level and an increase in T4 level, negatively influence the expression of the investigated liver CYP isoforms.
Our recent studies suggest that brain serotonergic system may be involved in the neuroendocrine regulation of cytochrome P450 expression. Intracerebral injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine affected serum hormone concentration and increased the expression and activity of the hormone-dependent isoforms CYP1A1/2, CYP2C11 and CYP3A1. Therefore, the aim of the present study was to investigate the effect of stimulation of brain serotonergic system on cytochrome P450 expression in the liver. The serotonin precursor 5-hydroxytryptophan (5-HTP) was injected for 5 days to the lateral ventricles of rat brain. Afterwards, the brain concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid 5-HIAA, serum hormone levels and liver cytochrome P450 expression and activity were measured. 5-HTP potently increased the concentration of serotonin and its metabolite 5-HIAA in all the brain structures studied including the hypothalamus. The brain concentrations of noradrenaline or dopamine and its metabolites were not changed in that structure. At the same time, a significant decrease in the serum concentration of the growth hormone and an increase in that of thyroxine were observed. In the liver, the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A was diminished, which positively correlated with a decrease in the respective CYP protein levels and a reduction in the mRNA levels of CYP1A2, CYP2A2, CYP2C11, CYP3A1 and CYP3A2. The obtained results provide evidence to prove that brain serotonergic system negatively regulates liver cytochrome P450 expression via endocrine system and suggest mechanisms by which this enzyme may be regulated by drugs with a serotonergic profile such as antidepressants.
Involvement of the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus in the central noradrenergic regulation of liver cytochrome P450
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It has been found that drugs acting on the central nervous system can influence the activity of cytochrome P450 [52]. Antidepressants enhance monoaminergic (i.e. noradrenergic, dopaminergic or serotonergic) neurotransmission in the brain, which affects the activity of the endocrine system, the latter being known to regulate the expression of cytochrome P450 [43,53–56]. The effect of antidepressant drugs on the expression of numerous CYP isoforms (CYP2B, CYP2C6, CYP2C11, CYP3A1/2 and CYP1A) has been described [40,41,52,57,58].
The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN-lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs.
The role of brain noradrenergic system in the regulation of liver cytochrome P450 expression
2013, Biochemical Pharmacology
Citation Excerpt :
In contrast to CYP2C11 and CYP3A isoforms, the increased activity of CYP1A may be ascribed to the enhancement of both mRNA and protein expression in the liver. This, in turn, may be due to the observed increase in corticosterone level and the reduced thyroid hormone (T4) concentration in the blood [62,63]. It has been shown that transcriptional activation of rat CYP1A1 gene requires the presence of arylhydrocarbon receptor (AhR) and is positively modulated by physiological concentrations of glucocorticoids via GRE sequences that are conserved within the first intron of CYP1A1 gene in rats, mice and humans [64–66].
The aim of the present study was to examine the effect of the brain noradrenergic system on the expression of cytochrome P450 in the liver. The experiment was carried out on male Wistar rats. Intracerebroventricular injection of the noradrenergic neurotoxin DSP-4 diminished noradrenaline level in the brain. Simultaneously, significant decreases in the serum concentration of the growth hormone, testosterone and the thyroid hormone thyroxine, as well as an increase in corticosterone level were observed. The concentrations of triiodothyronine and the cytokines interleukine 2 (IL-2) and 6 (IL-6) were not changed by DSP-4. The neurotoxin produced complex changes in the functioning of cytochrome P450. Significant decreases in the activity of liver CYP2C11 (measured as a rate of the 2α- and 16α-hydroxylation of testosterone) and CYP3A (measured as a rate of the 2β- and 6β-hydroxylation of testosterone) were found. In contrast, the activity of CYP1A (measured as a rate of caffeine metabolism) rose, while that of CYP2A (measured as a rate of the 7α-hydroxylation of testosterone), CYP2C6 (measured as a rate of the 7-hydroxylation of warfarin) and CYP2D (the 1′-hydroxylation of bufuralol) remained unchanged. The changes in the activity of CYP1A, CYP2C11 and CYP3A correlated positively with those in CYP protein levels and with the CYP mRNA levels of CYP1A1, CYP2C11 and CYP3A1/2 genes, respectively. The obtained results indicate an important role of the brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 expression, which may be of significance in pathological states involving this system, or during pharmacotherapy with drugs affecting noradrenergic transmission.
Cytochrome P450 is regulated by noradrenergic and serotonergic systems
2011, Pharmacological Research
Citation Excerpt :
Thus the expression of male CYP2A2, CYP2C13, CYP3A2 and 4A2, as well as CYP2B1/2, CYP3A1 and CYP3A18 dominant in males, depends on action of pulsatile GH secretion [11,13–19]. Thyroid hormones (triiodothyronine - T3 and thyroxine - T4) suppress the expression of CYP1A, CYP2A, CYP2B, and CYP3A [14,20–25], while the regulation of CYP2C11 expression seems to be largely independent of these hormones [26,27]. Besides endogenous hormones, the expression of CYP1A/2B/2C/3A is under the suppressive action of cytokines [28].
The aim of the present study was to ascertain whether the noradrenergic or serotonergic systems may affect the expression of liver cytochrome P450 (CYP). Rats were injected intraperitoneally with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, a noradrenergic neurotoxin) or p-chloroamphetamine (PCA, a serotonergic neurotoxin) or p-chlorophenylalanine (PCPA, an inhibitor of serotonin synthesis). One week after neurotoxin injection the levels of neurotransmitters (noradrenaline, dopamine, serotonin) and their metabolites were measured in brain structures, and the activity and protein levels of CYP isoforms were measured in the liver. In the brain, DSP-4 or PCA and PCPA selectively decreased noradrenaline or serotonin levels, respectively. In the liver, the applied neurotoxins evoked decrease in the activity of CYP2B, CYP2C11 and CYP3A (DSP-4, PCA, PCPA) and increase in the activity of CYP1A (PCA, PCPA), while the activity of CYP2A, CYP2C6 and CYP2D was not affected by the applied neurotoxins. Since the affected isoforms (CYP1A/2B/2C11/3A) are regulated by endogenous hormones (growth hormone, corticosterone, thyroid hormones), the latter being under control of the central nervous system, it is postulated that the brain noradrenergic and serotonergic systems are involved in the physiological regulation of liver CYP expression.
Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts:Mini rat, a transgenic rat carrying antisense RNA transgene for rat growth hormone
1999, Toxicology Letters
We investigated the characteristics of hepatic cytochrome P450s and flavin-containing monooxygenase 1 (FMO1) in male Nts:Mini rats, a Wistar/Jcl-derived transgenic rat strain showing less plasma GH concentration than the parental strain. The total hepatic P450 contents of Mini rats were significantly reduced. A suppression was observed in the activities and protein expression of male-specific P450s (CYP3A and CYP2C11) and was speculated to be a potential cause of the reduction in total P450 contents. The activity and protein expression of CYP2B1 were suppressed and those of CYP2E1 and CYP2B2 were enhanced. With the exception of our data on CYP2B1,these results largely agreed with previous reports concerning GH-depletion rat models (hypophysectomized rats, rats neonatally treated with glutamate, and dwarf rats), implying that the changes in Mini rats were caused by GH insufficiency. The liver FMO1 protein expression in Mini rats was higher than that in Wistar rats but the activity was comparable, suggesting that GH is not a positive regulator of FMO expression. With their insufficient but not depleted levels of plasma GH, Mini rats may thus become another candidate for use in the investigation of GH regulation of hepatic mixed-function monooxygenases.
Effect of thyroid hormones on flavin-containing monooxygenase activity in co-cultured adult rat hepatocytes
1998, Toxicology in Vitro
The regulation of flavin-containing monooxygenase (FMO) by thyroid hormones was examined under well defined in vitro conditions using adult male rat hepatocytes co-cultured with rat liver epithelial cells of primitive biliary origin. Serum free medium was used to avoid interferences from foetal bovine serum. The effect of thyroxine (T4) and its major metabolite l-triiodothyronine (T3) on FMO activity was estimated spectrophotometrically by measuring the rate of methimazole oxygenation. The highest non-cytotoxic doses of T3 and T4 that could be used in co-cultures were determined by measuring both lactate dehydrogenase leakage into the medium and microsomal protein content of the hepatocytes as a function of culture time. In addition, hormonal responsiveness of the in vitro system used was confirmed by malic enzyme activity measurements. Administration of 10 μm T3 or T4 was found to cause a significant decrease in FMO activity and content, suggesting a suppressive role of both hormones on the regulation of FMO activity in male rats.

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Thyroid hormone suppression of hepatic levels of phenobarbital-inducible P-450b AND P-450e and other neonatal P-450S in hypophysectomized rats

Abstract

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Jpn. J. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochem. Pharmacol.

Prog. Lipid Res.

J. Biochem.