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Drug-induced oxidative stress and toxicity.

Deavall DG, Martin EA, Horner JM, Roberts R - J Toxicol (2012)

Bottom Line: Species include oxygen radicals and reactive nonradicals.Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities.We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

View Article: PubMed Central - PubMed

Affiliation: Safety Assessment, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.

ABSTRACT
Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

No MeSH data available.


Related in: MedlinePlus

Molecular and cellular events by which oxidative stress in response to Dox, AZT, and cisplatin may result in toxicity. Dox, AZT, and cisplatin accumulation in cells may result in elevations in intracellular ROS. Dox may accumulate in cardiac cells by association with cardiolipin and generate ROS via reduction of molecular oxygen by the semiquinone free radical or by an iron II-Dox radical. Cisplatin may be transported into cells via the OCT transporters (e.g., in renal tubule cells) and elevate ROS levels via induction of NOXs. At the molecular level, ROS damage amino acids, lipid, and DNA. Mitochondrial dysfunction and associated alterations in energetics, together with effects on survival/apoptotic signaling cascades may lead to a proapoptotic response. These common mechanisms may be key to Dox-dependent cardiotoxicity, AZT-dependent skeletal myopathy, and cisplatin-dependent nephrotoxicity and ototoxicity described further in Section 3.
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fig3: Molecular and cellular events by which oxidative stress in response to Dox, AZT, and cisplatin may result in toxicity. Dox, AZT, and cisplatin accumulation in cells may result in elevations in intracellular ROS. Dox may accumulate in cardiac cells by association with cardiolipin and generate ROS via reduction of molecular oxygen by the semiquinone free radical or by an iron II-Dox radical. Cisplatin may be transported into cells via the OCT transporters (e.g., in renal tubule cells) and elevate ROS levels via induction of NOXs. At the molecular level, ROS damage amino acids, lipid, and DNA. Mitochondrial dysfunction and associated alterations in energetics, together with effects on survival/apoptotic signaling cascades may lead to a proapoptotic response. These common mechanisms may be key to Dox-dependent cardiotoxicity, AZT-dependent skeletal myopathy, and cisplatin-dependent nephrotoxicity and ototoxicity described further in Section 3.

Mentions: The extent to which mechanisms of drug-induced oxidative stress have been characterized varies. Metabolism of a drug may generate a reactive intermediate that can reduce molecular oxygen directly to generate ROS, as discussed below for doxorubicin. Chlorpromazine is an interesting example as photoactivation in skin is considered likely to lead to cutaneous phototoxicity (sunburn-like reaction and hyperpigmentation), which is a well-know adverse event associated with this compound [58]. Photodechlorination converts chlorpromazine to an excited state with subsequent energy transfer to molecular oxygen and generation of both excited singlet oxygen and superoxide species. These species may then react with DNA and macromolecules as described above and trigger adaptive or toxic responses in the skin as a result. For other drugs, there is evidence of elevation in cellular ROS in response to drug exposure, and evidence implicates ROS and oxidative stress in toxicity even if the mechanisms by which ROS are generated are characterized less fully. In this section, we discuss further the evidence for involvement of oxidative stress in drug-induced toxicities, using the examples of doxorubicin, azidothymidine, and cisplatin. In Figure 3, the common mechanisms by which oxidative stress in response to treatment with these drugs can lead to tissue-specific toxicities are presented.


Drug-induced oxidative stress and toxicity.

Deavall DG, Martin EA, Horner JM, Roberts R - J Toxicol (2012)

Molecular and cellular events by which oxidative stress in response to Dox, AZT, and cisplatin may result in toxicity. Dox, AZT, and cisplatin accumulation in cells may result in elevations in intracellular ROS. Dox may accumulate in cardiac cells by association with cardiolipin and generate ROS via reduction of molecular oxygen by the semiquinone free radical or by an iron II-Dox radical. Cisplatin may be transported into cells via the OCT transporters (e.g., in renal tubule cells) and elevate ROS levels via induction of NOXs. At the molecular level, ROS damage amino acids, lipid, and DNA. Mitochondrial dysfunction and associated alterations in energetics, together with effects on survival/apoptotic signaling cascades may lead to a proapoptotic response. These common mechanisms may be key to Dox-dependent cardiotoxicity, AZT-dependent skeletal myopathy, and cisplatin-dependent nephrotoxicity and ototoxicity described further in Section 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3420138&req=5

fig3: Molecular and cellular events by which oxidative stress in response to Dox, AZT, and cisplatin may result in toxicity. Dox, AZT, and cisplatin accumulation in cells may result in elevations in intracellular ROS. Dox may accumulate in cardiac cells by association with cardiolipin and generate ROS via reduction of molecular oxygen by the semiquinone free radical or by an iron II-Dox radical. Cisplatin may be transported into cells via the OCT transporters (e.g., in renal tubule cells) and elevate ROS levels via induction of NOXs. At the molecular level, ROS damage amino acids, lipid, and DNA. Mitochondrial dysfunction and associated alterations in energetics, together with effects on survival/apoptotic signaling cascades may lead to a proapoptotic response. These common mechanisms may be key to Dox-dependent cardiotoxicity, AZT-dependent skeletal myopathy, and cisplatin-dependent nephrotoxicity and ototoxicity described further in Section 3.
Mentions: The extent to which mechanisms of drug-induced oxidative stress have been characterized varies. Metabolism of a drug may generate a reactive intermediate that can reduce molecular oxygen directly to generate ROS, as discussed below for doxorubicin. Chlorpromazine is an interesting example as photoactivation in skin is considered likely to lead to cutaneous phototoxicity (sunburn-like reaction and hyperpigmentation), which is a well-know adverse event associated with this compound [58]. Photodechlorination converts chlorpromazine to an excited state with subsequent energy transfer to molecular oxygen and generation of both excited singlet oxygen and superoxide species. These species may then react with DNA and macromolecules as described above and trigger adaptive or toxic responses in the skin as a result. For other drugs, there is evidence of elevation in cellular ROS in response to drug exposure, and evidence implicates ROS and oxidative stress in toxicity even if the mechanisms by which ROS are generated are characterized less fully. In this section, we discuss further the evidence for involvement of oxidative stress in drug-induced toxicities, using the examples of doxorubicin, azidothymidine, and cisplatin. In Figure 3, the common mechanisms by which oxidative stress in response to treatment with these drugs can lead to tissue-specific toxicities are presented.

Bottom Line: Species include oxygen radicals and reactive nonradicals.Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities.We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

View Article: PubMed Central - PubMed

Affiliation: Safety Assessment, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.

ABSTRACT
Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

No MeSH data available.


Related in: MedlinePlus