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Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine.
Biochem Pharmacol. 2005 Apr 01; 69(7):1081-93.BP

Abstract

The objective of this work was to evaluate the possible in vitro interactions of S-adenosyl-l-methionine (SAM) and its metabolites S-(5'-Adenosyl)-l-homocysteine (SAH), 5'-Deoxy-5'-(methylthio)adenosine (MTA) and methionine with cytochrome P450 enzymes, in particular CYP2E1. SAM (but not SAH, MTA or methionine) produced a type II binding spectrum with liver microsomal cytochrome P450 from rats treated with acetone or isoniazid to induce CYP2E1. Binding was less effective for control microsomes. SAM did not alter the carbon monoxide binding spectrum of P450, nor denature P450 to P420, nor inhibit the activity of NADPH-P450 reductase. However, SAM inhibited the catalytic activity of CYP2E1 with typical substrates such as p-nitrophenol, ethanol, and dimethylnitrosamine, with an IC(50) around 1.5-5mM. SAM was a non-competitive inhibitor of CYP2E1 catalytic activity and its inhibitory actions could not be mimicked by methionine, SAH or MTA. However, SAM did not inhibit the oxidation of ethanol to alpha-hydroxyethyl radical, an assay for hydroxyl radical generation. In microsomes engineered to express individual human P450s, SAM produced a type II binding spectrum with CYP2E1-, but not with CYP3A4-expressing microsomes, and SAM was a weaker inhibitor against the metabolism of a specific CYP3A4 substrate than a specific CYP2E1 substrate. SAM also inhibited CYP2E1 catalytic activity in intact HepG2 cells engineered to express CYP2E1. These results suggest that SAM interacts with cytochrome P450s, especially CYP2E1, and inhibits the catalytic activity of CYP2E1 in a reversible and non competitive manner. However, SAM is a weak inhibitor of CYP2E1. Since the K(i) for SAM inhibition of CYP2E1 activity is relatively high, inhibition of CYP2E1 activity is not likely to play a major role in the ability of SAM to protect against the hepatotoxicity produced by toxins requiring metabolic activation by CYP2E1 such as acetaminophen, ethanol, carbon tetrachloride, thioacetamide and carcinogens.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA. andres.caro@mssm.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15763544

Citation

Caro, Andres A., and Arthur I. Cederbaum. "Inhibition of CYP2E1 Catalytic Activity in Vitro By S-adenosyl-L-methionine." Biochemical Pharmacology, vol. 69, no. 7, 2005, pp. 1081-93.
Caro AA, Cederbaum AI. Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. Biochem Pharmacol. 2005;69(7):1081-93.
Caro, A. A., & Cederbaum, A. I. (2005). Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. Biochemical Pharmacology, 69(7), 1081-93.
Caro AA, Cederbaum AI. Inhibition of CYP2E1 Catalytic Activity in Vitro By S-adenosyl-L-methionine. Biochem Pharmacol. 2005 Apr 1;69(7):1081-93. PubMed PMID: 15763544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. AU - Caro,Andres A, AU - Cederbaum,Arthur I, PY - 2004/11/11/received PY - 2005/01/12/accepted PY - 2005/3/15/pubmed PY - 2005/4/23/medline PY - 2005/3/15/entrez SP - 1081 EP - 93 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 69 IS - 7 N2 - The objective of this work was to evaluate the possible in vitro interactions of S-adenosyl-l-methionine (SAM) and its metabolites S-(5'-Adenosyl)-l-homocysteine (SAH), 5'-Deoxy-5'-(methylthio)adenosine (MTA) and methionine with cytochrome P450 enzymes, in particular CYP2E1. SAM (but not SAH, MTA or methionine) produced a type II binding spectrum with liver microsomal cytochrome P450 from rats treated with acetone or isoniazid to induce CYP2E1. Binding was less effective for control microsomes. SAM did not alter the carbon monoxide binding spectrum of P450, nor denature P450 to P420, nor inhibit the activity of NADPH-P450 reductase. However, SAM inhibited the catalytic activity of CYP2E1 with typical substrates such as p-nitrophenol, ethanol, and dimethylnitrosamine, with an IC(50) around 1.5-5mM. SAM was a non-competitive inhibitor of CYP2E1 catalytic activity and its inhibitory actions could not be mimicked by methionine, SAH or MTA. However, SAM did not inhibit the oxidation of ethanol to alpha-hydroxyethyl radical, an assay for hydroxyl radical generation. In microsomes engineered to express individual human P450s, SAM produced a type II binding spectrum with CYP2E1-, but not with CYP3A4-expressing microsomes, and SAM was a weaker inhibitor against the metabolism of a specific CYP3A4 substrate than a specific CYP2E1 substrate. SAM also inhibited CYP2E1 catalytic activity in intact HepG2 cells engineered to express CYP2E1. These results suggest that SAM interacts with cytochrome P450s, especially CYP2E1, and inhibits the catalytic activity of CYP2E1 in a reversible and non competitive manner. However, SAM is a weak inhibitor of CYP2E1. Since the K(i) for SAM inhibition of CYP2E1 activity is relatively high, inhibition of CYP2E1 activity is not likely to play a major role in the ability of SAM to protect against the hepatotoxicity produced by toxins requiring metabolic activation by CYP2E1 such as acetaminophen, ethanol, carbon tetrachloride, thioacetamide and carcinogens. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/15763544/Inhibition_of_CYP2E1_catalytic_activity_in_vitro_by_S_adenosyl_L_methionine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(05)00057-2 DB - PRIME DP - Unbound Medicine ER -