Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes

Laine, Jaana; Auriola, Seppo; Pasanen, Markku; Juvonen, Risto O.

doi:10.1080/00498250802512830

Cited by 225 publications

(123 citation statements)

References 32 publications

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“…However, whether there is some other antioxidant signals involved in the protection of CGA against AP-induced liver injury has not been identified. Liver CYP2E1, CYP1A2, and CYP3A4 have been reported to be the key metabolic enzymes responsible for metabolizing AP (Laine et al, 2009). In this present study, we observed the protection of CGA against AP-induced hepatotoxicity in vitro and in vivo, and then observed the potential effects of CGA on CYP2E1, CYP1A2, and CYP3A4 enzymatic properties and their expression, and finally observed the involvement of some antioxidant signals in the protection of CGA against AP-induced liver injury.…”

Section: Introductionsupporting

confidence: 65%

“…It has been reported that CYP2E1, CYP3A4, and CYP1A2 are the key CYP450 enzymes for the metabolic activation of AP in human liver, and that the metabolic product of AP in the liver will cause serious hepatotoxicity (Raucy et al, 1989;Laine et al, 2009). In addition, AP has been reported to be metabolized into AM404, which acts on transient receptor potential vanilloid 1 (TRPV1), cyclooxygenase (COX), and endogenous cannabinoid system, contributing to antipyretic and analgesic effects of AP (Högestätt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Pang

Sheng

Jiang

et al. 2015

J. Zhejiang Univ. Sci. B

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Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST) in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin (Prx) 1, 2, 3, 5, 6, epoxide hydrolase (Ephx) 2, and polymerase (RNA) II (DNA directed) polypeptide K (Polr2k), and nuclear factor erythroid-2-related factor 2 (Nrf2). In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury.

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Pang

Sheng

Jiang

et al. 2015

J. Zhejiang Univ. Sci. B

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“…Acetaminophen is also reported to be a CAII inhibitor [40]. Using human recombinant CYPs, 3A4 was found to be the most efficient in the generation of NAPQI, followed by CYP2E1 [65]. CYP1A1, CYP1A2, CYP2C19, and CYP2D6 had intermediate activity, while CYP2A6, CYP2B6, and CYP2C9 had weak activity.…”

Section: Results: Disproportionate Molecular Targets Identified By Damentioning

confidence: 99%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

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Drug features that are associated with StevensJohnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with druginduced adverse events. The information gained may contribute to systems biology disease models.

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“…We believe the reason for this is that kale ingestion inflular damage in humans and experimental animals (15,29). Previous reports (4,10,17,20,26) have shown that CYP3A4, CYP1A2, CYP2D6, and CYP2E1 are involved in the metabolism of AA. In addition, it has been reported that ITCs had an inhibitory effect on CYP activity (6,7,12,14,23).…”

Section: Resultsmentioning

confidence: 94%

Effects of kale ingestion on pharmacokinetics of acetaminophen in rats

et al. 2011

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Kale is a cruciferous vegetable (Brassicaceae) that contains a large amount of health-promoting phytochemicals. The chronic ingestion of cabbage of the same family is known to accelerate conjugating acetaminophen (AA) and decrease the plasma AA level. Therefore, we examined to clarify the effects of kale on the pharmacokinetics of AA, its glucuronide (AA-G) and sulfate (AA-S). AA was orally administered to rats pre-treated with kale or cabbage (2000 mg/kg/day) for one week. Blood samples were collected from the jugular vein, and the concentrations of AA, AA-G and AA-S were determined. In results, kale ingestion induced an increase in the area under the concentration-time curve (AUC) and a decrease in the clearance of AA, whereas cabbage had almost no influence. In addition, there were significant differences in the AUC of AA-G between the control and kale groups. mRNA expression levels of UDP-glucuronosyltransferases, the enzymes involved in glucuronidation, in the kale group were significantly higher than those in the control group. In conclusion, kale ingestion increased the plasma concentrations of both AA and AA-G. The results suggest that kale ingestion accelerates the glucuronidation of AA, but an increase of plasma AA levels has a different cause than the cause of glucuronidation.Kale (Brassica oleracea L. var acephala DC) is a leafy green vegetable belonging to the cabbage family (Brassicaceae) which has a high nutritional content because it is rich in phytochemicals, and contains high concentrations of minerals and vitamins, carotenoid, dietary fiber, and antioxidant compounds, including polyphenols and phenolic acids (9, 18). Some epidemiological studies have provided sound scientific evidence that the regular consumption of Brassicaceae, including cabbage, broccoli, cauliflower and brussel sprouts, may be highly effective in reducing cancer risk (1,22,24,30). Brassicaceae plants contain a high amount of specific phytochemicals known as glucosinolates, a large group of sulfur-containing glucosides. Upon the disruption of plant tissues (food processing, chewing, etc.), glucosinolates come into contact with plant myrosinase, and then myrosinase catalyzes the conversion of glucosinolates to isothiocyanates (ITCs). There are various kinds of ITCs, phenethyl ITC (cabbage, watercress), benzyl ITC (papaya), allyl ITC (black mustard), and sulforaphane (broccoli), which have pungent components and a strong flavor that stimulates people's appetite. It has been known that ITCs contribute to the chemoprevention function of Brassicaceae by inducing phase 2 detoxication enzymes (e.g., UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs)), and they have attracted intense research interest (2,5,8,13,21,28). Whereas, there is possibility that Brassicaceae plants promote the conjugation of some drugs, and then decrease effects of drugs. Previous study showed that a diet containing cabbage induced the conjugation of acetaminophen (AA),

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Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes

Cited by 225 publications

References 32 publications

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Effects of kale ingestion on pharmacokinetics of acetaminophen in rats

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