National Toxicology Program

National Toxicology Program
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Abstract from Report IMM20503 on Lovastatin

Range-Finding Report on the Immunotoxicity of Lovastatin in Female B6C3F1 Mice (CAS No. 75330-75-5)

Report Date: August 2012

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.


Abstract

Lovastatin, also know by the brand names Altocor and Mevacor, is a cholesterol-lowering agent isolated from a strain of Aspergillus terreus. LVS belongs to the inhibitory class of drugs known as the statins. After oral ingestion, LVS, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol (Alberts, 1990). Statins have been reported to have wide ranging immunomodulatory effects, including anti-inflammatory and pro-inflammatory effects, and inhibition of MHC class II and co-stimulatory molecules, including CD40 (Chow, 2009). In addition, some statins have been shown to be capable of skewing the immune response from a T-helper type 1 response towards a T-helper type 2 response (Chow, 2009). While LVS itself has not been shown to promote such a bias (Neuhaus et al., 2002), it has been shown to upregulate pro-inflammatory cytokine production (Sun and Fernandes, 2003).

The National Toxicology Program requested that a dose range-finding study be performed to establish the potential effects of LVS on the immune system. These studies were conducted in female B6C3F1 mice. The animals were exposed to LVS orally once each day for 28 days. Five LVS dose levels (0.5, 2, 5, 20, and 50 mg/kg) were utilized. LVS was prepared weekly as a suspension in the vehicle 0.5% methylcellulose.

Overall, exposure to LVS had no effects on body weight. Organ weights were not significantly affected when evaluated as either absolute or relative weight. Similarly, hematological parameters were not affected.

Seven functional assays, including the spleen Immunoglobulin M antibody-forming cell response to sheep red blood cells, natural killer cell activity assay, activity of the mononuclear phagocytic system, the mixed leukocyte response, and cytotoxic T lymphocyte activity assay were conducted. There were no significant dose-responsive effects associated with any of the assays. Mixed results were observed in the spleen cell proliferative response to anti-CD3 stimulation. In one study, no significant effects were observed, while a repeat study demonstrated significant decreases at the 20 and 50 mg/kg dose groups. Additionally, flow cytometric analyses were undertaken to determine the number and percentages of leukocytes in the spleen. Overall, there were only minor effects observed in the various cell types, and, where a significant effect was observed, it was not dose-responsive in nature. In two of the three assays used to evaluate humoral immunity (i.e., the AFC response and the sRBC enzyme-linked immunosorbent assay, no significant effects were observed following treatment with LVS. In the third assay (i.e., the keyhole limpet hemocyanin ELISA) ), serum anti-KLH IgM levels were decreased only at the high dose level (i.e., 50 mg/kg). Overall, LVS had little effect on the humoral immune component of the immune response.

In conclusion, the results of this study demonstrated that, under the experimental conditions used, LVS produced no toxicological effects and minimal effects on innate, humoral, or cell-mediated immunity in female B6C3F1 mice when administered daily for 28 days by oral gavage at doses up to and including 50 mg/kg.

References

Alberts A.W. (1990). Lovastatin and simvastatin – inhibitors of HMG CoA reductase and cholesterol biosynthesis. Cardiology, 77 Suppl 4:14-21.

Chow S.C. (2009). Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch Immunol Ther Exp, 57:243-251.

Neuhaus O., Strasser-Fuchs S., Fazekas F., Kieseier B.C., Niederwieser G., Hartung H.P., & Archelos J.J. (2002). Statins as immunomodulators: comparison with interferon-beta-1b in MS. Neurology, 59:990-997.

Sun D. & Fernandes G. (2003). Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production. Cell Immunol, 223: 52-62.


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