The quantification of cytochrome P-450 (CYP 3A4) mRNA in the blood of patients with viral liver diseases
Introduction
Cytochrome P-450 (CYP) is an important drug metabolic enzyme primary distributed in the liver [1]. The most highly expressed CYP is the CYP3A subfamily, which includes the isoforms 3A4, 3A5, 3A7, and 3A43. The most abundant CYP3A isoform expressed in the liver and gut is CYP 3A4 [2]. CYP 3A4 expression in liver and its enzymatic activity may vary between 20- and 50-fold among normal individuals [2], [3].
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are worldwide health problems. Chronic hepatitis (CH) due to HBV and HCV may progress to liver cirrhosis (LC) or hepatocellular carcinoma (HCC) over the course of 20–30 years. In LC, liver function, including CYP 3A4 enzymatic activity, is decreased [4]. In addition, CYP 3A4 is also a procarcinogen metabolizer [1] and thus may play a role in hepatocarcinogenesis. However, the level of CYP 3A4 expression in blood and liver and its role in viral liver diseases is unclear. To clarify whether CYP 3A4 expression in blood and liver is related to hepatitic activity, progression of viral liver diseases, and occurrence of HCC, we quantified CYP 3A4 mRNA in the blood and liver of patients with viral liver diseases.
Section snippets
Patients
The study population was comprised of 51 patients (40 males, 11 females, mean age ± SD: 52.4 ± 14.7 years, range: 22–77 years) including 6 with acute hepatitis (AH), 17 with CH, 12 with LC, and 16 with HCC, admitted to our hospital between February 2001 and September 2002, consecutively. The number of HBs antigen positive and HCV antibody positive patients in CH was 14 and 3, respectively, and was 9 and 3 in LC, and 14 and 2 in HCC. In AH, 1 patient was HBs antigen positive, 3 were HCV antibody
Results
CYP 3A4 mRNA could not be detected in the peripheral mononuclear cells or serum isolated from the 10 mL of blood from the normal controls, but was detectable in 10 mL of whole blood (1.6 ± 0.4) from the same subjects. The CYP 3A4 mRNA titer varied about 20 fold in the 12 normal subjects.
In the 7 CH and 3 LC patients, the CYP 3A4 mRNA titer in the blood correlated with that of the liver (r = 0.65, P < 0.05). Table 1 shows the CYP 3A4 mRNA titer in the blood of the various liver disease patients.
Discussion
Examination of CYP 3A4 activity in liver disease is difficult. Sumida reported that CYP 3A4 activity is related to the CYP 3A4 mRNA titer in the liver [8]. To investigate CYP 3A4 expression and its role in viral liver diseases, we determined the CYP 3A4 mRNA titer in whole blood and liver tissue. A close relationship was detected between the CYP 3A4 mRNA titers in blood and liver, suggesting that the CYP 3A4 mRNA titer in blood is a surrogate marker for the CYP 3A4 mRNA titer and enzymatic
References (23)
- et al.
Relationship between mRNA levels quantified by reverse transcription-competitive PCR and metabolic activity of CYP3A4 and CYP2E1 in human liver
Biochem. Biophys. Res. Commun.
(1999) - et al.
Cytochrome P450 regulation by hepatocyte nuclear factor in human hepatocytes: a study using adenovirus-mediated antisense targeting
Hepatology
(2001) - et al.
CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease
Hepatology
(2003) - et al.
Quantification of cytochrome P450 mRNAs in patients with suspected liver diseases as assessed by reverse transcriptase-polymerase chain reaction
J. Lab. Clin. Med.
(1999) - et al.
Quantitative analysis of constitutive and inducible CYPs mRNA expression in the HepG2 cell line using reverse transcription-competitive PCR
Biochem. Biophys. Res. Commun.
(2000) - et al.
Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes
Biochem. Biophys. Res. Commun.
(2000) - et al.
Interleukin-6, nitric oxide, ant the clinical and hemodynamic alterations of patients with liver cirrhosis
Am. J. Gastroenterol.
(1999) - et al.
Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region
Biochem. Biophys. Res. Commun.
(1999) - et al.
CYP3A genetics in drug metabolism
Nat. Med.
(2001) - et al.
Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians
J. Pharmacol. Exp. Ther.
(1994)
Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method
Pharmacogenetics
Cited by (12)
Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets
2013, Prostaglandins Leukotrienes and Essential Fatty AcidsCitation Excerpt :These differences in P450 expression levels may affect drug metabolism as well as endogenous substrate metabolism among different tissues. Some P450s, such as CYP3A4 and CYP1B1 [4,5], have been detected in human blood. Among blood cells, the CYP1A1, 2C9, 2C18, 2C19, 2J2, 2D6, 4A11 and 4F2 have been identified in lymphocytes and polynuclear leukocytes [6–8].
Construction and functional evaluation of a liver cell line tranfected with a vector expressing cytochrome P450 3A4 and glutathione-Stransferase A1
2012, World Chinese Journal of DigestologyAcute and long-term effects of cannabinoids on hypertension and kidney injury
2022, Scientific ReportsIncreased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin
2017, American Journal of Health-System PharmacyCase Series of HIV Infection-Associated Arteriopathy: Diagnosis, Management, and Outcome over a 5-Year period at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University
2015, International Journal of Lower Extremity WoundsEstablishment of cytochrome P450 3A4 and glutathione S-transferase A1-transfected human hepatoma cell line and functional analysis
2014, Genetics and Molecular Research