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Christopher Liddle

Publications and source records attributed to Christopher Liddle.

23 records · Page 2Linked to original sources
PubMed2002

Regulation of hepatic drug metabolism: role of the nuclear receptors PXR and CAR.

Recent advances in the molecular biology of nuclear receptors have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are able to act as sensors for lipophilic xenobiotics, including therapeutic drugs. These receptors in turn regulate enzymes and transporters involved in drug metabolism and disposition in an adaptive fashion. An unexpected finding was that the PXR was able to recognize bile acids; transgenic animals lacking this receptor are at increased risk of bile acid-induced liver injury. These findings provide new insights into hepatic drug metabolism as well as mechanisms regulating cholesterol and bile acid homeostasis.

Animals↗
PubMed2002

The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer.

CYP3A4 is involved in the metabolism of endogenous steroids, and an allelic variant, CYP3A4*1B, consisting of an A to G polymorphism within the 5'-flanking region termed the nifedipine-specific response element (NFSE) has been associated with high grade and advanced stage of prostate cancers. Because steroid hormone exposure is known to influence breast and ovarian cancer risk, we conducted case-control studies to assess the relationship between CYP3A4*1B and risk of breast or ovarian cancer. CYP3A4 NFSE genotype was determined in 951 breast cancer cases and 500 controls frequency matched for age and 488 ovarian cancer cases and 276 controls of similar age distribution. Case-control analyses and comparisons of genotype distributions were conducted by unconditional logistic regression. In addition, the functional significance of the CYP3A4*1B polymorphism was assessed by analysis of CYP3A4-reporter gene constructs transiently transfected into liver-derived cell lines and primary cultures of well-differentiated rat hepatocytes. The GG genotype was rare in all groups (0-0.4%). There was no risk of cancer associated with the AG/GG genotypes combined, with an OR (95% CI) of 0.86 (0.54-1.33) for breast cancer (P = 0.5), and 1.51 (0.80-2.89) for ovarian cancer (P = 0.2). Analysis of CYP3A4-luciferase constructs showed that CYP3A4*1B did not consistently affect reporter gene activity. Our data suggest that the CYP3A4*1B polymorphism is not associated with risk of breast or ovarian cancer. In support of this negative finding, in-vitro functional studies indicate that NFSE genotype is not a critical factor in the transcriptional activity of the CYP3A4 5'-flanking region, and is thus unlikely to modulate CYP3A4-mediated metabolism of steroids.

5' Untranslated Regions↗
PubMed2002

Changes in serum albumin during treatment of chronic hepatitis B with lamivudine: effects of response and emergence of drug resistance.

OBJECTIVES: In chronic hepatitis B patients treated with lamivudine, the incidence of drug resistance increases with the duration of therapy. The effect of drug resistance on hepatic synthetic function is not well defined. The aim of the present study was to assess the effect of lamivudine therapy on hepatic synthetic function in patients with moderately severe chronic hepatitis B and, particularly, to determine the effect of drug resistance. METHODS: Hepatic synthetic function was assessed using serial measurements of serum albumin in 38 patients (26 with cirrhosis) in an open-label treatment program. RESULTS: An initial antiviral response (hepatitis B virus [HBV] DNA undetectable by hybridization assay) occurred in all patients, and nine of 22 (41%) hepatitis B e antigen-positive cases underwent hepatitis B e antigen seroconversion. Among 29 patients with undetectable serum HBV DNA at the end of observation, the mean serum albumin concentration rose from 39.9 +/- 0.7 to 43.2 +/- 0.6 g/L, corresponding to a yearly increase of 1.85 g/L (p < 0.001). This was largely attributable to an increase among cirrhotic patients. Nine patients (24%) developed resistance to lamivudine, all after 12 months of treatment. Among them, the mean serum albumin concentration had increased from 39.6 +/- 1.2 to 42.9 +/- 0.8 g/L before resistance emerged, but then decreased to 39.3 +/- 1.7 g/L (p = 0.01) at the time of reappearance of HBV DNA. CONCLUSION: Suppression of viral replication by lamivudine improves hepatic synthetic function in chronic hepatitis B patients, but emergence of drug resistance is associated with a rapid decline in serum albumin, at least to pretreatment levels.

Adult↗
PubMed2002

Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor.

Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in adult human liver, is both constitutively expressed and transcriptionally activated by a variety of structurally diverse xenochemicals. In this study, we examined the role of the constitutive androstane receptor (CAR), a member of the steroid/retinoid/thyroid hormone receptor superfamily, in the transcriptional regulation of CYP3A4. Herein, we demonstrate that CAR is capable of trans-activating expression of the CYP3A4 gene, both in vitro and in vivo. Induction of CYP3A4 is dependent on cooperativity between elements within the promoter proximal region of the gene and the distal xenobiotic-responsive enhancer module. CAR responsiveness was shown to be primarily mediated by two high-affinity binding motifs located within the CYP3A4 gene 5'-flanking region, approximately 7720 and 150 bases upstream of the transcription initiation site. Importantly, the human CAR response elements also mediate trans-activation of CYP3A4 by the human pregnane X receptor, suggesting that interplay between these receptors is likely to be an important determinant of CYP3A4 expression.

Constitutive Androstane Receptor↗