Expression of cytochrome P450 1A1/2 and 3A4 in liver tissues of hepatocellular carcinoma cases and controls from Taiwan and their relationship to hepatitis B virus and aflatoxin B₁-and 4-aminobiphenyl-DNA adducts

Abstract

Cytochrome P450 enzymes play a major role in the metabolism of several of the chemical carcinogens involved in the development of hepatocellular carcinoma (HCC). To investigate by immunohistochemistry interindividual differences in these enzymes, polyclonal antisera and immunoperoxidase staining were used to detect the expression of CYP1A1/2 and 3A4 in 37 surgical control tissues and 105 tumour and adjacent nontumour tissues of HCC cases from Taiwan. There was variability in the expression and staining pattern for both CYP1A1/2 and 3A4 in all tissue types. In tissues from controls, there was no correlation between P450 expression and smoking history or hepatitis B virus antigen status. Since these samples had been previously analysed for the DNA adducts of aflatoxin B1 (AFB1), a dietary mould contaminant, and 4-aminobiphenyl (4-ABP), a component of cigarette smoke, we also investigated the relationship between P450 levels and DNA adducts. 4-ABP-DNA adducts were higher in tissues with elevated levels of CYP1A1/2 (p = 0.02). Overall there was no relationship between CYP1A1/2 or CYP3A4 and AFB1-DNA adducts in control tissues. Staining intensity for CYP1A1/2 and 3A4 followed the order: tumour tissues < control tissues < adjacent non-tumour tissues. CYP1A1/2 levels tended to be lower in tumour and adjacent non-tumour tissues than for CYP3A4. In HCC cases, 4-ABP-DNA adducts were higher in subjects with higher levels of CYP1A1/2, stratified by tissue type, but these differences were not significant. For CYP3A4, in contrast to control tissues, there was a significant association with AFB1-DNA adducts in tumour and adjacent non-tumour tissue of HCC cases. These results suggest that one factor influencing carcinogen-DNA adducts is levels of specific P450 enzymes. However, adduct formation in vivo is a complex processes dependent upon numerous genetic and environmental factors.

Biological Relevance of Adduct Detection to the Chemoprevention of Cancer

“…Indeed, the exo isomer of aflatoxin B 1 epoxide, formed by human cytochrome P450 3A4, is particularly genotoxic (41,42). In a recent study, higher levels of this cytochrome P450 isozyme have been found in liver tissue from aflatoxin B 1 -exposed cases of hepatocellular carcinoma than controls (43). The balance between activating and detoxifying enzymes may be influenced by chemopreventive agents such as oltipraz (see below) or indole-3-carbinol, which induces both cytochrome P450 and detoxification enzymes and prevents aflatoxin B 1 -induced hepatocarcinogenesis in rodents (44).…”

Liver-Targeted Drug Delivery Using HepDirect Prodrugs

“…Higher araCTP levels result because cell penetration is independent of nucleoside transporters and because prodrug cleavage generates araCMP, which both bypasses the rate-limiting kinase re-sponsible for the conversion of araC to araCMP, i.e., dCK, and avoids deamination by cytidine deaminase. Since primary liver tumors retain high levels of CYP3A4 activity (Zhang et al, 2000), MB07133 is expected to undergo conversion in hepatocarcinoma cells to araCTP, which in turn is expected to inhibit DNA polymerase activity and consequently inhibit DNA synthesis and tumor cell growth (Miura and Izuta, 2004).…”

Noninvasive, Accurate Diagnosis of Chronic Liver Diseases Using Whole-Transcriptome Profiling of Platelets

“…The DEGs at the LC-HCC stage are enriched in a metabolism-related pathway. Most clinically used drugs are metabolized by cytochrome P450, which has been best characterized in the liver (34) and plays a major role in the metabolism of several chemical carcinogens involved in the development of HCC (35). A previous study reported a substantial change in cytochrome P450 activities in patients with HCC (36).…”