Bioactivation of Minocycline to Reactive Intermediates by Myeloperoxidase, Horseradish Peroxidase, and Hepatic Microsomes: Implications for Minocycline-Induced Lupus and Hepatitis

Abstract

ABSTRACT:Of the tetracyclines, minocycline is unique in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. It is also unique among the tetracyclines in having a para-N,N-dimethylaminophenol ring. Many drugs that cause autoimmune reactions are oxidized to reactive metabolites by the myeloperoxidase (MPO) system of macrophages. In this study, we showed that minocycline is oxidized to reactive intermediates by MPO We were surprised to find that the same NAC adduct was not observed after oxidation of tetracycline with HOCl, even though this part of the tetracycline structure is the same as for minocycline. We propose that one or more of these reactive metabolites are responsible for the idiosyncratic drug reactions that are specific to this tetracycline.Minocycline (Fig. 1), a tetracycline antibiotic (Kamel et al., 2002), is used for the treatment of acne (Cullen and Cohan, 1976), infectious diseases, and rheumatoid arthritis. However, minocycline is associated with serious adverse reactions, which include hypersensitivity reactions (Antunes et al., 1999), a serum sickness-like reaction (Puyana et al., 1990), hepatitis (Hardman et al., 1996), and a drug-induced lupus-like reaction (Farver, 1997). The incidence of minocyclineinduced lupus is approximately 15 cases/100,000 prescriptions and is more common in women (Borchers et al., 2007). Patients treated with minocycline often develop perinuclear antineutrophilic cytoplasmic antibodies (P-ANCA, usually antimyeloperoxidase) (Dunphy et al., 2000), and in patients with minocycline-induced lupus, P-ANCA is present in 80% of cases (Sturkenboom et al., 1999).Minocycline-induced hepatitis can lead to hepatic failure requiring liver transplantation (Boudreaux et al., 1993). The incidence of minocycline-induced hepatitis in new users is approximately 1/10,000 patients (Seaman et al., 2001). Reports to the World Health Organization of the hepatic adverse drug reactions associated with the minocycline accounted for 6% (493) of all the minocycline-induced adverse drug reactions (8025) (Lawrenson et al., 2000). The reported cases of minocycline-induced hepatitis are characterized by autoimmune characteristics, including antinuclear antibodies and a very long duration of therapy (more than 1 year) (Lawrenson et al., 2000) before the onset of clinical signs of hepatitis (Knowles et al., 1996;Teitelbaum et al., 1998). There is a large amount of circumstantial evidence to support the hypothesis that most idiosyncratic drug reactions are caused by reactive metabolites (Lavergne et al., 2008). Cytochromes P450 (P450s) are likely responsible for the production of more reactive metabolites than any other enzyme; however, myeloperoxidase (MPO) is also capable of forming reactive metabolites, especially when the drug has an easily oxidized nitrogen (Uetrecht, 1992). The cells that contain MPO include neutrophils, macrophages, and other antigen-presenting cells. The formation of reactive metabolites by neutrophils has obvious implications for drug-induced agr...

Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor

“…It also remains possible that minocycline or a metabolite binds covalently to cellular proteins resulting in the presentation of a drug-peptide complex to T-cells via HLA-B* 35:02 , as appears to occur with flucloxacillin in HLA-B * 57:01 carriers (36). Evidence for the formation of a reactive intermediate(s) from minocycline but not other tetracyclines has been reported previously (37). Our group and others are planning additional in vitro experiments in patients with and without the HLA-B * 35:02 allele to follow-up on these preliminary studies.…”

Hepatotoxicity Due to Azole Antimycotic Agents in a HLA B*35:02-Positive Patient

“…This concept was described in flucloxacillin-associated DILI and HLA B*57:01 carriers: The drug-peptide complex has led to the activation of T cells (Monshi et al, 2013). Other discussed mechanisms for the hepatotoxic properties of minocycline include the formation of neoantigens by damaged hepatocytes (Urban et al, 2017), as well as an increased production of reactive intermediates (Mannargudi et al, 2009). It is interesting to note that the HLA B*57:01 allele is not only associated with flucloxacillin-induced liver injury, but also pazopanib-induced liver injury and abacavir hypersensitivity, suggesting that HLA allele associations are not specific for a single drug.…”

Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update

“…However, it is too early to take this as evidence against the inflammation hypothesis of schizophrenia because several trials that used minocycline in patients with rheumatoid arthritis 77 and amyotrophic lateral sclerosis [78][79][80] showed a trend towards symptom aggravation rather than improvement, while these 2 diseases are clearly associated with increased proinflammatory status in the brain. Several authors report that minocycline can trigger autoimmune diseases such as lupus erythematosus, arthritis, thyroiditis, and hepatitis, [81][82][83][84][85][86][87][88] suggesting that minocycline may also worsen proinflammatory and autoimmune processes.…”