Highly active antiretroviral therapy does not affect mitochondrial beta-oxidation of fatty acids: an in vitro study in fibroblasts.
Preeclampsia is a multifactorial pregnancy-specific disease. In some cases, severe preeclampsia and related disorders of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, low platelets syndrome are associated with inherited defects in mitochondrial beta-oxidation of fatty acids, especially a deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD). Recently, an unexplained increase in the incidence of preeclampsia has been documented in human immunodeficiency virus (HIV)-infected pregnant women on treatment with highly active antiretroviral therapy (HAART). We performed this study to determine if antiretroviral drugs affect mitochondrial beta-oxidation fatty acids in vitro. Two normal and 1 heterozygous LCHAD-deficient cell lines were exposed to up to 5 times the therapeutic concentrations of the following antiretroviral drugs: nevirapine, didanosine, lamivudine, and a combination of nelfinavir, zidovudine, and lamivudine. One homozygous LCHAD-deficient cell line served as the positive control. After exposure of the fibroblasts to these drugs for periods ranging from 2 to 10 days, accumulations of even-chain 3-hydroxy fatty acids (3-OH-C6 to 3-OH-C18) in the culture media were measured by stable-isotope dilution gas chromatography/mass spectrometry. Compared to the respective unexposed fibroblasts, there was no significant build-up of 3-hydroxy fatty acids in the culture media of normal or heterozygous LCHAD-deficient fibroblasts exposed to antiretroviral drugs. Our results show that the commonly used antiretroviral drugs do not adversely affect fatty acid oxidation in fibroblasts. Therefore, an altered fatty acid oxidation may not be the mechanism for the reported increased risk of preeclampsia in HIV-infected pregnant women on HAART.
Butt
Yasmeen M
YM
Department of Pathology, Children's Medical Center, USA.
Kamrudin
Samira A
SA
Rakheja
Dinesh
D
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D002460:Cell Line; D002849:Chromatography, Gas; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019829:Nevirapine / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011225:Pre-Eclampsia / Q000139:chemically induced; D011247:Pregnancy
D044966:Anti-Retroviral Agents; D005227:Fatty Acids; D019829:Nevirapine; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase