The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash

Abstract

Current advances in the study of cutaneous adverse drug reactions can be attributed to the recent understanding that the skin is both a metabolically and immunologically competent organ. The ability of the skin to serve as a protective barrier with limited drug biotransformation ability, yet highly active immune function, has provided insights into its biological capability. While the immune response of the skin to drugs is vastly different from that of the liver due to evolutionary conditioning, it frequently occurs in response to various drug classes and manifests as a spectrum of hypersensitivity reactions. The skin is a common site of adverse and idiosyncratic drug reactions; drug-specific T-cells, as well as involvement of an innate immune response, appear to be key mechanistic drivers in such scenarios. Association of other factors such as human leukocyte antigen (HLA) polymorphisms may play a significant role for particular drugs. This review aims to integrate emerging findings into proposed mechanisms of drug metabolism and immunity in the skin that are likely responsible for rashes and other local allergic responses. These unique biological aspects of the skin, and their translation into implications for drug development and the use of animal models, will be discussed.

<p>COVID’s Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19</p>

“…109 By inhibiting AT1, ARBs decrease experimental myocarditis. 110 RAS-driven T-cell-mediated effects in the heart, coupled with T-cell-mediated skin effects, which are also well described, 111,112 could potentially explain the pediatric Kawasaki-like condition linked to SARS2. 16 Besides ischemic and inflammatory tissue destruction, another aspect of cardiac pathology in COVID-19 is the development of arrhythmias and sudden cardiac death.…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…Skin rash is a highly reported adverse effect likely because it is visible to the patient, even if it is not usually severe. Additionally, as a barrier between the host and the environment, the skin has high immune activity and contains a number of immune cells including macrophages, Langerhans cells, mast cells, and multiple lymphocytes (Sharma et al, 2019). Although the skin has very low cytochrome P450 activity relative to the liver (Rolsted et al, 2008), it contains other enzymes capable of xenobiotic metabolism, such as sulfotransferases and acetyltransferases, which can bioactivate drugs and generate covalently modified proteins (Baker et al, 1994;Dooley et al, 2000;Bhaiya et al, 2006;Luu-The et al, 2009).…”

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

“…Metabolism is highly varied due to polymorphic enzymes, with cytochrome P450 (CYP450) enzymes responsible for 90% of drug metabolism (Lynch and Price, 2007) and for which allelic variants are described from poor to ultrarapid metabolisers (Zanger and Schwab, 2013). While metabolic activity of skin is considered limited (Sharma et al, 2019), keratinocytes show capacity to metabolize and present drug-derived antigens (Reilly et al, 2000;Roychowdhury and Svensson, 2005). Several studies now investigate metabolic variants associated with DHR, most notably for phenytoin, predominantly oxidized to an inactive metabolite by CYP2C9 with minor contribution by CYP2C19.…”