Activity of sulfotransferase 1A1 is dramatically upregulated in patients with hepatocellular carcinoma secondary to chronic hepatitis B virus infection

Abstract

The phase I metabolizing enzyme and phase II metabolizing enzyme play vital roles in carcinogenesis, but little is known about the changes of their activities in patients with hepatocellular carcinoma (HCC) secondary to chronic hepatitis B virus (HBV) infection. In this study phenacetin, a probe drug (1 g for men and 0.85 g for women orally), was applied for the detection of sulfotransferase 1A1 (SULT1A1) and cytochrome P4501A2 (CYP1A2) activities in 82 healthy participants and 148 HCC, 106 cirrhosis, and 41 chronic hepatitis B patients. In addition, a prospective cohort study for susceptibility to HCC was performed in 205 patients with cirrhosis secondary to chronic HBV infection. Compared with the healthy participants, SLUT1A1 activity increased by 9.7-fold in the HCC patients (P < 0.01). CYP1A2 activity did not significantly differ between the healthy participants and HCC patients. CYP1A2 activity decreased by 91.2% (P < 0.01) and 67.7% (P < 0.05) in the patients with cirrhosis and chronic hepatitis B, respectively; SULT1A1 activity did not increase significantly. During an approximate 2-year follow up, three of the 46 cirrhosis patients with elevated SULT1A1 activity and normal CYP1A2 activity developed HCC, but none of the 159 cirrhosis patients used as parallel controls did (P = 0.012). These results indicate that SLUT1A1 activity is dramatically upregulated in patients with HCC secondary to chronic HBV infection. The upregulation of SULT1A1 activity is not caused by the tumor itself. The interaction between SULT1A1 and CYP1A2 can play an important role in hepatocarcinogenesis in the Chinese population. (Cancer Sci 2010; 101: 412-415) T he phase I metabolizing enzyme and phase II metabolizing enzyme play vital roles in carcinogenesis and tumor response to anticancer therapy, (1)(2)(3) but little is known about the changes of their activities in patients with hepatocellular carcinoma (HCC). In previous investigations, we found that the phenacetin metabolism was different between healthy participants and HCC patients.(4) There were significant differences not only in the pharmacokinetics of phenacetin, but also in its metabolites.Phenacetin O-deethylation is a marker reaction of cytochrome P4501A2 (CYP1A2) activity. As a probe drug, phenacetin has been extensively used to study the effects of genetic and environmental factors on CYP1A2 activity.(5-7) After the oral administration of phenacetin, its O-deethylated metabolite acetaminophen is mostly transformed into glucuronide acetaminophen or sulfate acetaminophen by hepatic UDPglucuronosyltransferases (UGT) and sulfotransferase 1A1 (SULT1A1), then rapidly excreted by the kidney.(8,9) Therefore, the ratio of urine glucuronide acetaminophen to sulfate acetaminophen (RUGSA) can be applied to the detection of hepatic SULT1A1 activity.Growing evidence shows that the gene-gene and gene-environment interactions involved in the metabolism of carcinogens can increase the risk of cancer, including colorectal, pancreatic, endometrial, breast, and urothelial cancer. ...

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Expression of sulfotransferase SULT1A1 in cancer cells predicts susceptibility to the novel anticancer agent NSC-743380

“…Indeed, members of the SULT1A subfamily have been found to be highly expressed in breast cancer cell lines but were not detected in normal human mammary epithelial cells [ 34 ]. The expression of SULT1A1 was readily detectable in primary breast cancer tissues but not in neighboring normal tissues [ 35 ], and SULT1A1 activity was drastically higher in hepatocellular carcinoma patients [ 36 ]. Patients with liver cirrhosis who had higher SULT1A1 activity had a higher risk of developing hepatocellular carcinoma than did such patients with normal SULT1A1 activity.…”

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“…Wang et al found a decrease of 68% in CYP1A2 activity in 41 patients with chronic hepatitis B virus, whereas Morcos et al observed that in chronic hepatitis C patients, CYP3A activity reduced 37% in 35 hepatitis C treatment‐naive patients and reduced 54% in hepatitis C‐treated null responders …”