Abstract
Inhibition of cytochrome P450 (CYP) alters the pharmacokinetic parameters of the drug and causes drug–drug interactions. Salicylic acid been used for the treatment of colorectal cancer (CRC) and chemoprevention in recent decades. Thus, the aim of this study was to examine the in vitro inhibitory effect of salicylic acid on CYP2E1 activity in rat liver microsomes (RLMs) using high-performance liquid chromatography (HPLC). High-performance liquid chromatography analysis of a CYP2E1 assay was developed on a reversed phase C18 column (SUPELCO 25 cm × 4.6 mm × 5 µm) at 282 nm using 60% H2O, 25% acetonitrile, and 15% methanol as mobile phase. The CYP2E1 assay showed a good linearity (R2 > 0.999), good reproducibility, intra- and inter-day precision (<15%), acceptable recovery and accuracy (80–120%), and low detection (4.972 µM and 1.997 µM) and quantitation limit values (15.068 µM and 6.052 µM), for chlorzoxazone and 6-hydroxychlorzoxazone, respectively. Salicylic acid acts as a mixed inhibitor (competitive and non-competitive inhibition), with Ki (inhibition constant) = 83.56 ± 2.730 µM and concentration of inhibitor causing 50% inhibition of original enzyme activity (IC50) exceeding 100 µM (IC50 = 167.12 ± 5.460 µM) for CYP2E1 enzyme activity. Salicylic acid in rats would have both low and high potential to cause toxicity and drug interactions with other drugs that are substrates for CYP2E1.
Highlights
IntroductionMembers of the cytochrome P450 (CP450) superfamily are known as phase 1 enzymes and play a key role in the biotransformation of a large number of endogenous (steroids, hormones, bile acids, fatty acids) and exogenous (toxic chemicals, drugs, carcinogens, environmental pollutants) compounds to a more hydrophilic form [1]
Members of the cytochrome P450 (CP450) superfamily are known as phase 1 enzymes and play a key role in the biotransformation of a large number of endogenous and exogenous compounds to a more hydrophilic form [1]
The aim of this study is to investigate the inhibitory effect of salicylic acid on the metabolism of the
Summary
Members of the cytochrome P450 (CP450) superfamily are known as phase 1 enzymes and play a key role in the biotransformation of a large number of endogenous (steroids, hormones, bile acids, fatty acids) and exogenous (toxic chemicals, drugs, carcinogens, environmental pollutants) compounds to a more hydrophilic form [1]. Statistical results showed that more than 90% of marketed drugs are metabolized by P450s [2]. CYP substrate may alter their metabolism, causing a drug–drug interaction [2]. Drug interactions take place when a certain drug interacts with another drug [3]. These interactions can result in the changing activity of one or both drugs and lead to adverse side effects [4]. Statistical evidence has shown that nearly 20–40% of elderly people in developing countries have drug–drug interactions due to poly-therapy [5]
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