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Biomedical subjects

T E Nicholson

Publications and source records attributed to T E Nicholson.

5 recordsLinked to original sources
PubMed2001

Role of cytokines in the lipopolysaccharide-evoked depression of cytochrome P450 in the brain and liver.

A role for cytokines as mediators of the depression in cytochrome P450 activity in brain and liver during CNS inflammation is proposed. Lipopolysaccharide (LPS) was given directly into the lateral ventricle of the brain to mimic a localized CNS infection. CYP1A activity and protein in both brain and liver were depressed in response to this treatment. The administration of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interferon-gamma (IFN-gamma) directly into the lateral ventricle emulated the effects of LPS on CYP1A activity only in the brain. In contrast, these centrally administered cytokines did not produce a concomitant loss of CYP1A activity in the liver. Significant levels of several cytokines (TNF-alpha, IL-1beta, and IFN-gamma) were produced in the serum of animals following intracerebroventricular (i.c.v.) administration of LPS. This production of peripheral cytokines by LPS could not be mimicked by the i.c.v. injection of IL-1beta or TNF-alpha. These results suggest that induction of cytokines in the brain may play a direct role in the depression of CYP1A activity in the CNS following the administration of LPS into the lateral ventricle. The production of cytokines within the brain does not appear to participate in the signaling process in the brain that leads to the concomitant loss of CYP1A activity in the liver. The subsequent production of cytokines in peripheral tissues, however, does appear to play a role in the loss of cytochrome P450 in the liver.

Animals↗
PubMed2001

Gene structure and expression of the mouse adipocyte enhancer-binding protein.

The adipocyte enhancer-binding protein (AEBP1) is a transcriptional repressor with carboxypeptidase activity. AEBP1 expression is down-regulated during adipogenesis. Aortic carboxypeptidase-like protein (ACLP) is a non-nuclear isoform of AEBP1 that has an N-terminal extension of 380 amino acids. ACLP expression is up-regulated during vascular smooth muscle cell differentiation. To gain insight into the regulation of AEBP1 isoform expression, we have determined the structural organization of the mouse AEBP1 gene. This gene extends over 10 kb, has 21 exons, and gives rise to two mRNAs (AEBP1 and ACLP). The 9th intron is retained in the mature AEBP1 transcript. Thus, ACLP encodes an additional 380 amino acids N-terminal to the first ATG codon of AEBP1 which is located in exon 10. RT-PCR experiments showed that both transcripts are expressed ubiquitously in all mouse tissues examined, while Western blot analysis suggested that expression is translationally regulated. Our results provide evidence that two isoforms of AEBP1 with very different functions are produced by an alternative splicing mechanism. This represents a new example of regulation of subcellular localization by protein truncation.

Amino Acid Sequence↗
PubMed2000

Hepatic and central nervous system cytochrome P450 are down-regulated during lipopolysaccharide-evoked localized inflammation in brain.

The effect of central nervous system inflammation on the levels and activity of hepatic and brain cytochrome P450 were examined in the rat. Brain ethoxyresorufin dealkylkase (EROD) was depressed during localized inflammatory responses evoked by lipopolysaccharide (LPS) injected into the lateral ventricle. This loss was accompanied by a concomitant loss of EROD activity and cytochrome P450 in liver. Similar losses in hepatic enzyme were observed for benzyloxy-resorufin and pentoxy-resorufin dealkylase (CYP2B) and chlorzoxazone hydroxylation (CYP2E). Protein levels of CYP2D and CYP2E1 but not CYP1A also were depressed. Similar i.p. doses of LPS had no effect on hepatic cytochrome P450, indicating that the hepatic effect was not caused by LPS leakage from the central nervous system. Also in support of this contention is that heat shock protein 27 was expressed throughout the brain by LPS given i.c. v. but was undetectable in the liver. Tumor necrosis factor-alpha given i.c.v. depressed EROD activity in the brain but this was not accompanied by a concomitant loss in the liver. Hepatic EROD did respond to the i.p. injection of tumor necrosis factor-alpha. The LPS-evoked loss in hepatic cytochrome P450 could not be prevented by blocking beta-receptor-mediated sympathetic nerve activity. This study demonstrates that localized inflammatory responses in the brain cause a concomitant down-regulation of cytochrome P450 and drug-metabolizing activity in the liver and the brain. The effect on brain cytochrome P450 may be regulated via cytokine-mediated pathways but signaling to the liver does not involve a cytokine-mediated pathway nor a beta-receptor-mediated sympathetic nerve pathway.

Adrenergic beta-Antagonists↗
PubMed1999

Modulation of cytochrome P450 by inflammation in astrocytes.

Activation of systemic host defense mechanisms results in the down-regulation of cytochrome P450 enzymes in the liver. This occurs for various induced and constitutive isoforms of cytochrome P450 in response to cytokines such as IFNs, IL-1, IL-6, and TNF-alpha, which are produced during infection. Although the levels of cytochrome P450 in brain regions are low, the enzymes are regionally distributed and may play a critical role in the activation or degradation of drugs and chemicals in localized areas. If activation of the immune response in the CNS by LPS modulates the activity of cytochrome P450 forms in the brain, this may alter normal metabolic pathways or contribute to drug or chemical toxicity. This hypothesis was addressed by examining the effect of LPS on a major cytochrome P450 form in isolated astrocytes obtained from newborn rats. These cells were shown to express CYP1A1/2 when induced by dibenz[a, h]anthracene (DBA) as determined by enzyme activity, immunohistochemistry, and Western blotting. The treatment of these cells with LPS significantly attenuated the activity of these enzymes but had no effect on CYP1A1/2 protein levels as determined by Western blotting. The lack of effect by detoxified LPS indicated the requirement of the lipid A region on LPS to stimulate this response. Pentoxifylline (PNTX) prevented the LPS evoked decrease in CYP1A1/2 activity suggesting that cytokine release was a required component of this effect in astrocytes. These results indicate that stimulation of the immune response by LPS in isolated astrocytes decreases CYP1A1/2 activity. The release of cytokines is implicated in this effect and thought to participate in the functional inhibition of the enzyme as no effect on CYP1A1/2 protein levels was observed.

Animals↗