The Chemical Biology of Naphthoquinones and Its Environmental Implications

Abstract

Quinones are a group of highly reactive organic chemical species that interact with biological systems to promote inflammatory, anti-inflammatory, and anticancer actions and to induce toxicities. This review describes the chemistry, biochemistry, and cellular effects of 1,2- and 1,4-naphthoquinones and their derivatives. The naphthoquinones are of particular interest because of their prevalence as natural products and as environmental chemicals, present in the atmosphere as products of fuel and tobacco combustion. 1,2- and 1,4-naphthoquinones are also toxic metabolites of naphthalene, the major polynuclear aromatic hydrocarbon present in ambient air. Quinones exert their actions through two reactions: as prooxidants, reducing oxygen to reactive oxygen species; and as electrophiles, forming covalent bonds with tissue nucleophiles. The targets for these reactions include regulatory proteins such as protein tyrosine phosphatases; Kelch-like ECH-associated protein 1, the regulatory protein for NF-E2-related factor 2; and the glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase. Through their actions on regulatory proteins, quinones affect various cell signaling pathways that promote and protect against inflammatory responses and cell damage. These actions vary with the specific quinone and its concentration. Effects of exposure to naphthoquinones as environmental chemicals can vary with the physical state, i.e., whether the quinone is particle bound or is in the vapor state. The exacerbation of pulmonary diseases by air pollutants can, in part, be attributed to quinone action.

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

“…As shown in Scheme 1B, there is little doubt that activation of both AhR and Nrf2 mediated by NQs derived from naphthalene causes increased levels of phase-I enzymes (e.g., CYP1A1), phase-II enzymes (e.g., aldo-keto reductases and UDPglucuronosyltransferases) and phase-III transporters (e.g., multi-drug resistance associated proteins). We therefore speculate that NQs would be unique metabolites that facilitate eventually the metabolism of its parent compound (i.e., naphthalene) associated with detoxification and excretion into extracellular space (Abiko et al, 2011;Kumagai et al, 2012;Miura et al, 2011) (Scheme 1B).…”

“…Of toxicological interest, it is well known that benzene and naphthalene undergo conversion by photooxidation and/or metabolic activation to yield quinone species that are able to modify protein thiols, leading to the formation of protein adducts (Kumagai et al, 2012). A variety of quinones, including 1,4-benzoquinone (1,4-BQ), 1,2-naphthoquinone (1,2-NQ), and 1,4-NQ are found in diesel engine exhaust, burning coal, cigarette smoke (Eiguren-Fernandez et al, 2010;Batterman et al, 2012;Wallace, 1989) and as metabolites during exposure of experimental animals and cultured cells (Wilson et al, 1996).…”

“…Butylated hydroxyanisol (BHA) and tert-butyl-1, 4-hydroquinone (TBHQ), which are used as a food and cosmetic additive to preserve oils, are metabolized to tertbutyl-1,4-benzoquinone (TBQ) (Verhagen et al, 1989;Snyder and Hedli, 1996). We found that 1,2-NQ and TBQ with α,β-unsaturated carbonyl groups, are able to modify cellular proteins with reactive thiol groups and activate electrophilic signal transduction pathways, such as protein phosphatase 1B (PTP1B)/epidermal growth factor receptor (EGFR) signaling and Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathways (Kumagai et al, 2012). These observations led us to the hypothesis that chemical modification of cellular proteins could modulate their function(s), thereby changing cellular homeostasis processes mediated by them.…”

A comparison of the effects of 1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone (lawsone) on indole-3-acetic acid (IAA)-induced growth of maize coleoptile cells

“…As compounds with remarkable chemical and structural properties, naphthoquinones have been the focus of the attention of scientists for a long time. The biological activity of naphthoquinones is primarily based on two primary mechanisms-one is the covalent modification of biological molecules at their nucleophilic sites, such as the thiols in proteins and glutathione (GSH), in which quinones act as electrophiles, while the other mechanism consists of redox cycling, in which reactive oxygen species (ROS) are generated (reviewed in El-Najjar et al 2011;Klotz et al 2014;Kumagai et al 2012). Naturally occurring naphthoquinones such as juglone (5-hydroxy-1,4-naphthoquinone), lawsone (2-hydroxy-1,4-naphthoquinone), plumbagin (2-methyl-5-hydroxy-1,4-naphthoquinone), naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) and others along with their synthetic derivatives have been studied intensively for many years in biology, medicine, agriculture and industry.…”

Preparation and Antimicrobial Activity of Rosin-based Carbamate Group-containing Quaternary Ammonium Salt Derivatives

“…Therefore, numerous efforts have been devoted to the development of new antibacterial agents (Wilson 2009;Kumagai et al 2012;Lin et al 2013;Fosso et al 2012). Among them, quaternary ammonium salt-containing cationic compounds have attracted considerable attention due to their robust and broad-spectrum antibacterial activities (Wynne et al 2011;Fouda et al 2013;Chanawanno et al 2010).…”