VOL. 1, No. 2 / 3, July 2004

J. Beltowski [2004] Med Hypotheses Res 1: 187-206.

Why Statins Have No Effect on Plasma Asymmetric
Dimethylarginine (ADMA) Level? ― The Possible Role
of Paraoxonase and Protein Homocysteinylation

Jerzy Beltowski*

Department of Pathophysiology, Medical University, Lublin, Poland

Abstract.  Statins (3-hydroxy 3-methylglutarylcoenzyme A reductase inhibitors) are
widely used in the treatment of cardiovascular diseases. In addition to reducing plasma
cholesterol, they exert pleiotropic effects on inflammatory reaction, coagulation,
fibrinolysis, smooth muscle cells, oxidative stress, and others. Asymmetric
dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is synthesized
by methylation of protein arginine residues, released during proteolysis, and degraded by
dimethylarginine dimethylaminohydrolase (DDAH). Hyperlipidemia and oxidative stress
increase ADMA production and impair its metabolism. Although statins improve lipid
profile and attenuate oxidative stress, they do not change plasma ADMA, which suggests
that these drugs may also have some opposite undesirable effect on its metabolism. Recent
studies suggest that hyperhomocysteinemia increases ADMA level. Homocysteine may be
converted to homocysteine thiolactone (HTL) by methionyl-tRNA synthetase. HTL binds
to lysine groups of proteins in the process referred to as protein homocysteinylation,
leading to decrease in their biological activity. Apart from total homocysteine level, the
amount of HTL is regulated by paraoxonase 1 (PON1) which hydrolyzes it to
homocysteine. Both in vitro and in vivo studies suggest that statins can decrease PON1
activity. It is possible that statins, by inhibiting PON1, increase the level of HTL leading to
homocysteinylation of DDAH, and thus reduce its activity. This undesirable mechanism
could oppose positive effect on ADMA metabolism resulting from hypolipidemic and
antioxidant properties of statins, resulting in no net changes in plasma ADMA

*Address all correspondence to: Dr. Jerzy Beltowski, Department of Pathophysiology,
Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland.
Phone: +48-81-7425837. Fax: +48-81-7425828. E-Mails:

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