The Difference Between Polymyxin B and Polymyxin E in Causing Skin Hyerpigmentation

Abstract

As we all know, Coronavirus Disease 2019 spread all over the world and had became a public international event of global concern. Among Coronavirus Disease 2019 patients in China, two doctors, Yi Fan and Weifeng Hu, were noticed with their skin pigmentary disorder due to polymyxin B. However, we found that polymyxin E has almost no reports of skin hyperpigmentation, but polymyxin B was reported about skin hyperpigmentation, although the number of relevant reports was small, what causes the difference between the polymyxin B and polymyxin E? Polymyxin is a general term for a group of basic peptide antibiotics, including A, B, C, D and E mainly. At present, the two commonly used clinically are polymyxin B and polymyxin E. The mechanism of polymyxin B causing skin hyperpigmentation may include the following aspects: 1. Polymyxin B activates mast cells to release histamine, which binds to the H₂ receptor on the surface of melanocytes inducing the stimulation of melanin synthesis Polymyxin B is a mast cell activator that binds to non-selective G protein-coupled receptors on the surface of mast cells, activates subsequent intracellular signaling pathways, and induces mast cells to degranulate and release histamine (Bushby and Green, 1955; Ferry et al., 2002; Morrison et al., 1974; Morrison et al., 1978; Zhan et al., 2019). Histamine is an inflammatory mediator involved in stimulating melanin production. Histamine binds to the H₂ receptor on the surface of melanocytes in the basal layer to induce the production of cyclic adenosine monophosphate and the activation of protein kinase a in melanocytes, which leads to phosphorylation of members of the cyclic adenylate response element binding protein transcription factor family. Cyclic AMP response element binding protein activates a variety of genes and induces the transcription of a variety of enzymes and proteins related to melanin synthesis. Eventually leads to increased melanin synthesis in the cytoplasm (Yoshida et al., 2020). Polymyxin E can also release histamine equivalent to polymyxin B (Bushby and Green, 1955), the reason why polymyxin E does not lead to skin hyperpigmentation is not very clear, the difference of amino acid at position 6 between the two drugs and the lower conversion rate of polymyxin E in vivo are possible explanation. According to the research, colistin methanesulfonate (CMS) as the prodrug is predominantly cleared by renal excretion, with only a relatively small fraction of the dosage converted to the active antibacterial in renally healthy individuals (Li et al., 2004; Li et al., 2006), it is evident that in patients with moderate to good renal function, administration of a daily dose of colistin base activity (CBA) at the upper limit of the current product-recommended dose range (300 mg CBA per day) was not able to generate plasma colistin concentrations that would be expected to be reliably efficacious (Garonzik et al., 2011). Is the concentration of polymyxin E not enough to activate mast cells to release enough histamine for inducing the stimulation of melanin synthesis? Further study is worthy. 2. The skin inflammation process is related to the activation of melanocytes Histological and immunohistochemical results of pigmented skin in patients with polymyxin B treatment showed an abundant melanocyte-pigmented dendritic network. Langerhans cells’ hyperplasia and dermal IL-6 overexpression were also found, presumably for an inflammatory process due to polymyxin B use (Mattos et al., 2016; Li et al., 2020; Wen et al., 2020); At the same time, although hyperpigmented skin did not show signs of inflammationby clinical inspection, under microscopic view the dermis contained mild-to- moderate perivascular inflammatory infiltrate of lymphocytes and histiocytes. Langerhans cells are antigen-presenting cells, which play an important role in skin immunity and inflammation. The proliferation of Langerhans cells in the epidermis of patients with polymyxin B induced-pigmentation indicates that polymyxin B can induce the inflammatory process of the skin. In addition to its known inflammatory effects, IL-6 also inhibits the proliferation and melanogenesis of human melanocytes, When the skin is hyperpigmented, IL-6 is often feedback overexpression which may be for regulation (Jawdat et al., 2004; Mattos et al., 2017). At the same time, studies have shown that mast cell-derived factors (including histamine) can stimulate Langerhans cell migration and are related to the melanin production pathway (Miori et al., 1990). Matzneller et al. reported that polymyxin E could decrease inflammatory cytokines, including IL-6, in the blood of L lipopolysaccharide-challenged healthy volunteers in a model of human endotoxiemia (Matzneller et al., 2017). And according to the newest report, it was showed that polymyxin E can’t regulate the expression of the inflammatory cytokine IL6, IL6 mRNA expression levels were not changed after administration of polymyxin E (Ubagai et al., 2021). According to these findings, the effects of polymyxin B and polymyxin E on IL6 are different. We speculate that it may explain the difference in pigmentation between the two drugs. 3. Oxidative stress is also considered to be one of the mechanisms of pigmentation (Zavascki et al., 2016) Ahmed et al. (2017) studied the effect of polymyxin B on human lung epithelial cells A549, and the results showed that polymyxin B induced oxidative stress and loss of mitochondrial membrane potential. Compared to untreated control cells, after 8 h treatment, the cellular oxidative stress increased around 1.9-fold and 3.8-fold for 1.0 and 2.0 mM of polymyxin B, respectively, which increased up to 2.6-fold and 4.7-fold at 24 h correspondingly. The article also mentioned that the hydrophobicity of the 6-phenylalanine in the structure of polymyxin B and the cationic form under physiological conditions play a key role in cytotoxicity and...