Screening for Naturally Occurring Inhibitors of Arylamine N-Acetyltransferase 1 Activity

Abstract

Most chemical carcinogens are not active in their original forms but required

bioactivation to highly reactive metabolites. The phase I and phase II enzymes play

important role in carcinogen activation. Arylamine N-acetyltransferases (NATs) are

phase II enzymes existed as two isoforms, NAT1 and NAT2. NAT enzymes catalyse

the biotransformation of many primary amines, hydrazines and their N-hydroxylated

metabolites, thereby play role in both the detoxification and metabolic activation of

numerous xenobiotics. Chemoprotection strategies against cancers usually include

the inhibition of various steps in metabolic activation. There were many reports

demonstrated that flavonoid had tumor prevention effect. In this study, the

chemopreventive agents of interest were focused primarily on some abundant natural

products which are found in fruits, vegetables, and teas as part of normal human diets.

The chemical classes employed in this study include polyphenol of small molecules

i.e. caffeic acid and ferulic acid; flavonoids i.e. quercetin, genistein, silymarin, tea

catechin and coumarins. Some nonsteroidal anti-inflammatory drugs which were

previously reported possessing NAT1 inhibition activity such as aspirin, paracetamol

and diclofenac were also included. This study was aimed to screen the inhibitory

action of these compounds in vitro on NAT1, since NAT1 enzyme is expressed

widely in the body. The sources of enzymes were from human extra-hepatic bile duct

carcinoma cell line (KMBC) and surgical liver specimens from cholangiocarcinoma

patients. NAT1 activity was determined by using para-aminobenzoic acid (PABA) as

a test substrate and was analysed by the high performance liquid chromatography

method. This study showed that caffeic acid, (-)epigallocatechin gallate, quercetin

and taxifolin showed strong NAT1 inhibition activity, whereas, tyramine and

tryptamine, the substrates of alkylarylamine N-acetyltransferase had only slightly

inhibitory effects. This study suggest that natural products with potent NAT

inhibitory activity may be useful in cancer chemoprevention