It is almost universally thought that modulation of immune function by tryptophan (Trp) metabolites involves activation of the aryl hydrocarbon receptor (AhR) mainly by kynurenine (Kyn), based on enhanced expression of cytochrome P-450 enzymes and their increased activities in cell systems and in vivo. However, DiNatale et al. (Toxicol. Sci. 2010; 115: 89-97) reported the failure of Kyn at 10 M to activate the AhR, whereas a similar concentration of kynurenic acid (KA) was effective. The recent study by Solvay et al (J Immunother Cancer 2023; 11: e006728) called into question the direct link between Kyn and the AhR and demonstrated down regulation of the AhR by Trp. In the present study, we have performed for the first time molecular docking in silico to the human AhR of the above and a range of other Trp metabolites produced in the various degradative pathways and by gut microbiota. We demonstrate that, of 29 Trp metabolites, only Kyn and 3-hydroxykynurenine fail to dock to the AhR and propose that AhR activation by Kyn is an indirect effect mediated by KA. The strongest docking is observed with FICZ (6-Formylindolo[3,2-b]carbazole), cinnabarinic acid, 5-hydroxytryptophan, N-acetyl serotonin and indol-3-yllactic acid. We propose that Trp, which docks strongly to the AhR is an AhR antagonist. Differences in AhR activation by Trp metabolites in cell systems and in vivo may be determined by the prevailing physiological conditions. The strong docking of 5-hydroxyindoles to the AhR may underpin the effects of serotonin pathway metabolites on biological processes.

Background and purpose: Bilirubin toxicity in newborn infants leading to kernicterus disturbs immune and neuronal functions through proinflammatory cytokines and a hyperglutamatergic state. Tryptophan metabolism along the kynurenine pathway may underpin both features. Phototherapy of neonatal hyperbilirubinemia (NNH) converts bilirubin to harmless products, mainly lumirubin. Lumirubin possesses protective properties, though its precise mechanism(s) of action is less understood. The tryptophan metabolite and photooxidation product 6-formylindolo[3,2-b]carbazole (FICZ) may also be formed during NNH phototherapy. Experimental approach: We have explored the basis of potential mechanisms of lumirubin and FICZ actions by their molecular docking to the following receptors: the aryl hydrocarbon (AhR), NMDA, kainate and GABA receptors. We compared their docking to the AhR with those of bilirubin and biliverdin and the potent AhR agonists FICZ, indirubin and 2,3,7,8-Tetrachlorodibenzo-p-dioxin and their docking to the other receptors with those of kynurenic (KA) and quinolinic (QA) acids. Key results: lumirubin and FICZ dock very strongly to the AhR, whereas biliverdin and bilirubin do not. Both lumirubin and FICZ also dock strongly to the NMDA and GABA receptors, as do KA and QA. Conclusions and implications: AhR activation by lumirubin may form the basis of NNH phototherapy. FICZ is also likely to play a role in NNH phototherapy. Interaction of lumirubin and FICZ with glutamate and GABA receptors may underpin antagonism of the excitotoxicity of kernicterus. Development of lumirubin- and FICZ-based pharmaceuticals may advance NNH therapy. Interaction of KA and QA with GABA receptors requires investigation at the pharmacological and behavioural levels.

Background and purpose: COVID-19 induces a proinflammatory environment that is stronger in cases requiring intensive care. Overexpression of the aryl hydrocarbon receptor (AhR) by COVID-19 may activate nuclear poly (ADP-ribose) polymerase 1 (PARP 1) thereby inducing cell death by NAD+ and ATP depletion. The purpose of this review is to propose PARP 1 inhibition as a COVID-19 therapy, starting with nicotinamide. Experimental approach: Evidence for the above effects of COVID-19, other coronaviruses and lung conditions will be reviewed. Key results: A proinflammatory environment characterises all the above conditions irrespective of severity. The AhR is overexpressed by various coronaviruses, the pneumovirus respiratory syncytial virus (RSV) and in chronic obstructive pulmonary disease (COPD) patients. PARP 1 is overexpressed in COPD and possibly also asthmatic patients. Conclusions: It is almost certain that PARP 1 is overexpressed by COVID-19. A sequence of events involving PARP 1 and culminating in patient mortality is proposed. PARP 1 inhibition should be the focus of COVID-19 therapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but the highly desirable biochemical and activity profiles of the NAD(P)+ precursor and PARP 1 inhibitor nicotinamide justify its use, initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors (once their efficacy is proven) or other therapies. Implications: Preventing death from COVID-19 infection with a widely available vitamin-like substance with a unique biochemical and activity profile can present a great clinical advance worldwide.

COVID-19 patients in China exhibit a proinflammatory environment that is stronger in severe cases requiring intensive care. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is over-expressed in a variety of coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation, which leads to cell death mainly by depleting NAD+ and ATP, is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide, which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines, and is effective against HIV infection. Its unique biochemical properties qualify nicotinamide for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors.