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Environmental exposure to cadmium (Cd) or lead (Pb) is independently associated with increased risks of type 2 diabetes, and chronic kidney disease. The aim of this study was to examine the effects of concurrent exposure to these toxic metals on the risks of diabetes and kidney functional impairment. The Cd and Pb exposure levels among study subjects were low to moderate, evident from the means for blood concentrations of Cd and Pb ([Cd]b and [Pb]b) of 0.59 µg/L and 4.67 µg/dL, respectively. Of 176 study subjects (mean age 60), 71 (40.3%) had abnormally high fasting plasma glucose levels. Based on their [Cd]b and [Pb]b, 53, 71, and 52 subjects were assigned to Cd and Pb exposure profiles 1, 2, and 3, respectively. The diagnosis of diabetes was increased by 4.2-fold in those with an exposure profile 3 (p = 0.002), and by 2.9-fold in those with the estimated glomerular filtration (eGFR) ≤ 60 mL/min/1.73 m2 (p = 0.029). The prevalence odds ratio (POR) for albuminuria was increased by 5-fold in those with plasma glucose levels above kidney threshold of 180 mg/dL (p = 0.014), and by 3.1-fold in those with low eGFR) (p = 0.050). Collectively, these findings suggest that the Cd and Pb exposure profiles equally impact kidney function and diabetes risk.

The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1–4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5–8 from V. cinerea, and acetylenic thiophenes 9–11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic KI values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32–15.4 and 0.92–8.67 µM, respectively, while those of thiophenes were 0.11–1.01 and 0.67–0.97 µM, respectively.

Human cytochrome P450 CYP2A6 and CYP2A13 catalyze nicotine metabolisms and mediate activation of tobacco-specific carcinogens including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we found rhinacanthins A, B, and C isolated from Rhinacanthus nasutus potentially inhibited coumarin 7-hydroxylation mediated by reconstituted purified recombinant CYP2A6 and CYP2A13. Rhinacanthins A-C are mechanism-based inactivators of CYP2A6 and CYP2A13 as they cause concentration, time and NADPH-dependent inhibition. Among the three rhinacanthins, rhinacanthin-B possessed highest inhibitory potency against CYP2A13 with apparent KI and kinact of 0.16 µM and 0.1 min(-1), respectively, while values of 0.44 µM and 0.12 min(-1) were found against CYP2A6. Rhinacanthin-C had least inhibition potency, with apparent KI and kinact of 0.97 µM and 0.07 min(-1) for CYP2A6, respectively, and values of 1.68 µM and 0.05 min(-1) for CYP2A13. Rhinacanthin-A inhibited CYP2A6 and CYP2A13 with apparent KI values of 0.69 and 0.42 µM, respectively and apparent kinact of 0.18 and 0.06 min(-1), respectively. The inhibition of both enzymes by rhinacanthins A-C could not be prevented by addition of trapping agents or reversed by dialysis or potassium ferricyanide. These findings demonstrated that rhinacanthins A-C, which are 1,4-naphthoquinone derivatives, irreversibly inhibited CYP2A6 and CYP2A13 in a mechanism-based inhibition mode.

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