Immune response to xenobiotics in the skin: from contact sensitivity to drug allergy

Khan, Farah; Roychowdhury, Sanjoy; Gaspari, Anthony A.; Svensson, Craig K.

doi:10.1517/17425255.2.2.261

Cited by 14 publications

(6 citation statements)

References 111 publications

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“…This potentially contributes to the clinically observed toxicities. Little is known about ERL-induced Stevens-Johnson syndrome and toxic epidermal necrolysis, but these syndromes are considered immunogenic, are commonly drug-induced, and drugs commonly associated with initiating these toxicities do not share common targets (Khan et al, 2006). Many compounds that are reported to induce Stevens-Johnson syndrome are associated with metabolic activation to form reactive intermediates, such as carbamazepine, diclofenac, penicillin, modafinil, acetaminophen, ibuprofen, and phenytoin (Neuman and Nicar, 2007;Locharernkul et al, 2008;Levi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Kamenecka²,

Cameron

2010

Drug Metab Dispos

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ABSTRACT:The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL) is approved for treatment of non-small-cell lung cancer. Numerous reports of ERL-associated toxicities are consistent with immune-mediated toxicity, including drug-induced hepatitis, interstitial lung disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Although the mechanism of toxicity has not been established, we present evidence that reactive intermediates are formed during the metabolism of ERL, which can covalently conjugate to the cysteine group of the peptide-mimetic GSH. Seven ERL-GSH conjugates were identified in incubations with hepatic microsomes. Cytochrome P450 (P450)-dependent adducts are proposed to be formed via reactive epoxide and electrophilic quinone-imine intermediates. In incubations of human liver microsomes, intestinal microsomes, pulmonary microsomes, and recombinant P450s, CYP3A4 was the primary enzyme responsible for the bioactivation of ERL; however, CYP1A1, CYP1A2, CYP3A5, and CYP2D6 were capable of catalyzing the bioactivation as well. During the metabolism of ERL, CYP3A4 and CYP3A5 are irreversibly inactivated by ERL in a time-and concentration-dependent manner. Inactivation was not dependent on oxidation of the ERL alkyne group to form a reactive oxirene or ketene, as shown by synthesizing analogs where the alkyne was replaced with a cyano group. CYP1A1, CYP1A2, and CYP2D6 were not inactivated despite catalyzing the formation of ERL-GSH adducts.Erlotinib (ERL) is a reversible inhibitor of the epidermal growth factor receptor tyrosine kinase (HER1/EGFR) and was approved for the second-and third-line treatment of non-small-cell lung cancer in 2005 (Siegel-Lakhai et al., 2005). Clinical trials indicate that ERL provides a survival benefit after failure of first-or second-line chemotherapy as a single agent and in the treatment of advanced pancreatic adenocarcinomas together with chemotherapy (Tang et al., 2006;Moore et al., 2007). Although having therapeutic benefit, treatment with ERL has been associated with life-threatening adverse effects, including drug-induced hepatitis (Liu et al., 2007b;Ramanarayanan and Scarpace, 2007;Saif, 2008;Pellegrinotti et al., 2009), interstitial lung disease (Liu et al., 2007a;Makris et al., 2007), and the severe skin disorders Stevens-Johnson syndrome and toxic epidermal necrolysis (Chou et al., 2006;Lübbe et al., 2008;Bovenschen and Alkemade, 2009). In September 2008, OSI Pharmaceuticals and Genentech (www.fda.gov/downloads/safety/medwatch/safetyinformation/ safetyalertsforhumanmedicalproducts/ucm135238) reported a pharmacokinetic study of 15 patients with advanced solid tumors and moderate liver impairment. During the study, one patient died from hepatorenal syndrome and another died because of progressive liver failure, and both deaths were attributed to ERL.In humans, ERL is extensively metabolized, predominantly by CYP3A4 and to a lesser extent by CYP1A2 and the inducible isoform CYP1A1 (Ling et al., 2006;Li et al., 2007), with metabolites exc...

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Kamenecka²,

Cameron

2010

Drug Metab Dispos

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“…In contrast, knowledge of the mechanisms of T cell-mediated allergies to orally or parenterally administered drugs is still only limited because of the variety of the clinical presentations of drug-induced diseases and of the lack of appropriate experimental models. Therefore, the mechanisms by which haptens provoke ACD after epicutaneous administration have served as a paradigm of how similar reactions to haptens may occur after systemic routes [56].…”

Section: Pathophysiology Of T Cell-mediated Drug Allergymentioning

confidence: 99%

Role of T cells in nonimmediate allergic drug reactions

Rozières

Vocanson

Saïd

et al. 2009

Current Opinion in Allergy &Amp; Clinical Immunology

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Nonimmediate allergic drug reactions are mediated by T cells and mostly affect the skin. Nonimmediate allergic drug reactions comprise several diseases ranging from the frequent and benign maculo-papular exanthema to the severe and rare toxic epidermal necrolysis. Progress in the knowledge of the pathophysiology of nonimmediate allergic drug reactions comes from a better understanding of the mechanisms of drug recognition by T cells and from a careful analysis of the phenotype and functions of CD4+ and CD8+ T cells infiltrating the skin lesions. Recent studies have confirmed that the different clinical forms of nonimmediate allergic drug reactions are associated with distinct types of T cell-mediated skin inflammation. However, CD8+ T cells appear as major effector T cells in most of the nonimmediate allergic drug reactions. Future studies to analyze the early cellular and molecular events leading to the development of the allergic skin reaction will be helpful in order to define diagnostic and therapeutic targets.

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“…Many drugs are known to provoke immune responses in the skin when applied topically or administered systemically. Studies of contact sensitivity have shown the importance of immune events in the skin itself for the provocation of a hypersensitivity reaction in the skin (Khan et al, 2006). Essential for initiation of such reactions is the activation of resident dendritic cells (i.e., LCs).…”

Section: Clinical Implications Of Drug Metabolism In Skinmentioning

confidence: 99%

Biotransformation of Drugs in Human Skin

Svensson

2008

Drug Metab Dispos

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ABSTRACT:Although it is the largest organ of the human body, skin is often not considered in discussions of drug metabolism. However, there is growing evidence that most common drug-metabolizing enzymes are expressed in the skin. Evidence for expression of cytochromes P450, flavin monooxygenases, glutathione-S-transferases, N-acetyltransferases, and sulfotransferases in human skin and skin cells are presented. Additional discussion is focused on the evidence of actual metabolism of drugs. Finally, the potential clinical implications of metabolism within the skin are discussed briefly.Representing the largest organ in the human body, skin provides an important barrier role in protecting the body from external chemicals and pathogens that would otherwise impair critical functions needed for survival. Comprised of a complex cellular network, skin is capable of many metabolic functions common to visceral organs, including the biotransformation of drugs that penetrate through its most external layer. In addition to being an important target for pharmacotherapy, delivery through the skin is increasingly used as an effective means of delivering drugs to the systemic circulation. It is also evident that biotransformation within the skin may be an essential step to manifesting cutaneous toxicity to certain drugs and chemicals. Hence, an understanding of the capacity and impact of drug biotransformation within skin is an important component in assessing pharmacotherapy directed to or through the cutaneous environment. In the present article, discussion will be limited to evidence for biotransformation of drugs generated specifically in human skin or skin cells. Although many investigations have probed the ability of skin from numerous species to metabolize a variety of environmental chemicals, the focus of the present review is on evidence for metabolism of therapeutic agents. The reader is referred to the recent review of Oesch et al. (2007) for a comparison of xenobiotic-metabolizing enzymes in the skin of various species. Overview of the Structure and Function of SkinExisting as a dynamic and flexible barrier, human skin serves a multifaceted role as the organ with the greatest exposure to the external environment. In addition to providing the primary means for tactile evaluation of the immediate surroundings, skin serves a critical role in thermoregulation of the body. The plethora of infectious diseases with cutaneous manifestations attests to the important sentinel role of skin in protecting the body from bacterial, fungal, and viral pathogens. Although this diversity of function is recognized, it is not surprising that skin is populated by numerous types of specialized cells (see Table 1) that enable dynamic interaction with the internal and external environment. Because studies assessing the role of skin in drug metabolism often use model cells, it is important to begin this review with a brief discussion of skin structure and function.Three identifiable layers comprise human skin: epidermis, dermis, and hypodermi...

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Immune response to xenobiotics in the skin: from contact sensitivity to drug allergy

Cited by 14 publications

References 111 publications

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Role of T cells in nonimmediate allergic drug reactions

Biotransformation of Drugs in Human Skin

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