Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion

Chariot, Patrick; Drogou, Irène; Lacroix-Szmania, I de; Eliezer‐Vanerot, Marie‐Christine; Chazaud, Bénédicte; Lombès, Anne; Schaeffer, A; Zafrani, Élie Serge

doi:10.1016/s0168-8278(99)80020-8

Cited by 235 publications

(140 citation statements)

References 32 publications

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“…Stavudine (d4T) and zidovudine (AZT) were being taken as a component of HAART by many of our patients, and both drugs have been clearly associated with steatosis in the setting of lactic acidosis. 26,27 Stavudine was also recently found to be specifically associated with steatosis in coinfected patients. 20 When we analyzed the potential relationship between HAART duration and/or specific individual HIV medications with steatosis in our study, we were unable to demonstrate any such associations.…”

Section: Discussionmentioning

confidence: 99%

Hepatic steatosis in HIV/hepatitis C coinfection: Prevalence and significance compared with hepatitis C monoinfection

et al. 2005

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Liver disease in patients coinfected with HIV and hepatitis C virus (HCV) has received increasing attention in recent years. Steatosis is accepted as an important contributor to liver disease in patients with HCV, but despite coinfected patients having several reasons to have steatosis, the prevalence and significance of such changes has received scant attention. We examined steatosis in an unselected cohort of coinfected patients and compared its prevalence and predictors with findings in monoinfected patients, where these relationships have been established. We studied 92 coinfected and 372 monoinfected patients undergoing staging liver biopsy. Baseline characteristics of the two groups differed significantly, pointing at different contributors to steatosis in each. Histological inflammation and fibrosis were very similar in the two groups, but steatosis was less in coinfected patients. Steatosis had a univariate association with fibrosis in both groups, but retained a multivariate association only in monoinfected patients. Other multivariate predictors of steatosis in monoinfected patients were the accepted variables of elevated body mass index, male sex, and genotype 3a infection, as well as age. In coinfected patients, however, age was the only multivariate predictor. Undetectable HIV viral load was associated with steatosis in coinfected patients in univariate analysis, but highly active antiretroviral therapy or its individual components could not be initially linked to steatosis. In conclusion, steatosis is less common in HIV/ HCV coinfected patients than similar HCV monoinfected patients, and predictors of steatosis differ between the two groups. (HEPATOLOGY 2005;42:310-316.)

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Section: Discussionmentioning

confidence: 99%

Hepatic steatosis in HIV/hepatitis C coinfection: Prevalence and significance compared with hepatitis C monoinfection

et al. 2005

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“…During the pre-highly active antiretroviral therapy (HAART) era, AZT monotherapy in AIDS patients was closely associated with myopathy, cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10]. Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15].…”

Section: Discussionmentioning

confidence: 99%

“…AZT capitalizes on human immunodeficiency virus's (HIV) unique method of replication by inhibiting the viral reverse transcriptase, which blocks the life-cycle of HIV and effectively slows the progression of AIDS. When given in monotherapy at high doses over long periods of time, AZT is known to cause damage to many tissues, including a mitochondrial skeletal muscle myopathy, a dilated cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10][11]. These conditions are related to AZT use and not to the progression of AIDS since when patients experiencing one or more of these adverse effects discontinued AZT therapy, the adverse effects would resolve [8,9].…”

Section: Introductionmentioning

confidence: 99%

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Lynx

Bentley

McKee

2006

Biochemical Pharmacology

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Abstract3′-Azido-3′-deoxythymidine (AZT) is a staple of highly active antiretroviral therapy (HAART). Prior to HAART, long-term use of high-dosage AZT caused myopathy, cardiomyopathy, and hepatotoxicity, associated with mitochondrial DNA depletion. As a component of HARRT, AZT causes cytopenias and lipodystrophy. AZT-5′-triphosphate (AZTTP) is a known inhibitor of the mitochondrial polymerase γ and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart mitochondria, AZT phosphorylation beyond AZT-5′-monophosphate (AZTMP) was not detected. Rather, AZT was shown to be a more potent inhibitor of thymidine phosphorylation (50% inhibitory concentration (IC 50 ) of 7.0 ± 1.0 μM) than AZTTP is of polymerase γ (IC 50 of >100 μM), suggesting that depletion of mitochondrial stores of TTP may limit replication. This work has investigated whether an identical mechanism might account for the hepatotoxicity seen with long-term use of AZT. Isolated rat liver mitochondria were incubated with labeled thymidine or AZT, and the rate and extent of phosphorylation were determined by HPLC analysis of acid-soluble extracts of the incubated mitochondria. The results showed that in the phosphorylation of thymidine to TMP, liver mitochondria exhibit a higher V max and K m than heart mitochondria, but otherwise heart and liver mitochondria display similar kinetics. AZT is phosphorylated to AZTMP, but no further phosphorylated forms were detected. In addition, AZT inhibited the production of TTP, with an IC 50 of 14.4 ± 2.6 μM AZT. This is higher, but comparable to, the results seen in isolated rat heart mitochondria. KeywordsAZT; Liver mitochondria; Thymidine; Mitochondrial toxicity; Thymidine kinase 2; Reverse transcriptase inhibitors Abbreviations AIDS, acquired immunodeficiency syndrome; AZT, 3′-azido-3′-deoxythymidine; AZTDP, 3′-azido-3′-deoxythymidine-5′-diphosphate; AZTMP, 3′-azido-3′-deoxythymidine-5′-monophosphate; AZTTP, 3′-azido-3′-deoxythymidine-5′-triphosphate; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; IC 50 , 50% inhibitory concentration; S.E.M., standard error of mean

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“…Once AZT is converted into its 5'-O-triphosphate analog by cellular kinases, it inhibits HIV reverse transcriptase, a key factor in the initiation of HIV replication, and thus terminates DNA chain synthesis from viral RNA inside the infected cells. 4 The utility of AZT is limited by its toxic effect on bone marrow, 5 hepatic abnormalities, 6 limited brain uptake, 7 short half-life in plasma, 8 high susceptibility to catabolism 9 and rapid progress of resistance by HIV-1. 10,11 For these reasons, numerous chemical strategies have been developed by medicinal scientists to design prodrugs of AZT, in order to increase its therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

“…We here report the synthesis, characterization, anti-HIV activity, cytotoxicity in cell cultures and enzymatic stability of novel AZT derivatives (4)(5)(6)(7), and of two known compounds, a tosyl (2) and a tricyclic analog (3), prepared by a simpler procedure than that previously reported. 14 Vol.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiretroviral evaluation of derivatives of zidovudine

Raviolo

Trinchero-Hernández

Turk

2009

J. Braz. Chem. Soc.

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Uma série de novos carbamatos de zidovudina (AZT, 1) foi sintetizada, caracterizada e avaliada em relação a sua atividade anti-HIV e citotoxicidade. O grupo hidroxila da posição 5' do AZT foi derivatizado usando-se N, N'-carbonildiimidazol e diferentes aminas para gerar os respectivos 5'-O-carbamatos. Além disso, dois derivados já conhecidos foram sintetizados, um 5'-O-tosilato e um derivado tricíclico (AZT-Cycl), empregando-se métodos mais rápidos e simples do que os previamente reportados. Embora os novos derivados tenham apresentado menor toxicidade do que o AZT, essa redução na citotoxicidade foi concomitante com a marcada diminuição para inibir a replicação do vírus, com exceção do AZT-Cycl, o qual, mesmo apresentando IC 50 = 1 µmol L -1 , não demonstrou sinais de citotoxicidade com valores de CCID 50 (µmol L -1 ) > 1000.A series of zidovudine (AZT, 1) derivatives have been synthesized and their anti-HIV activity and cytotoxicity have been determined. The 5'-OH function of AZT was derivatized using N, N'-carbonyldiimidazole and different amine compounds leading to their 5'-O-carbamates. In addition, two known AZT derivatives 5'-O-tosylate and a tricyclic one (AZT-Cycl) were also obtained by a simpler procedure than those previously reported. Although these AZT derivatives were less toxic than AZT, their reduced cytotoxicity was concomitant with an inability to inhibit HIV-1 replication, except in the case of AZT-Cycl, which showed an IC 50 = 1 µmol L -1 without cytotoxicity with values of CCID 50 (µmol L -1 ) > 1000.

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Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion

Cited by 235 publications

References 32 publications

Hepatic steatosis in HIV/hepatitis C coinfection: Prevalence and significance compared with hepatitis C monoinfection

Hepatic steatosis in HIV/hepatitis C coinfection: Prevalence and significance compared with hepatitis C monoinfection

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Synthesis and antiretroviral evaluation of derivatives of zidovudine

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