Gender Influence on XOR Activities and Related Pathologies: A Narrative Review

Abstract

Taking into account the patient's gender is the first step towards more precise and egalitarian medicine. The gender-related divergences observed in purine catabolism and their pathological consequences are good examples of gender medicine differences. Uric acid is produced by the activity of xanthine oxidoreductase (XOR). The serum levels of both XOR activity and uric acid differ physiologically between the genders, being higher in men than in women. Their higher levels have been associated with gout and hypertension, as well as with vascular, cardiac, renal, and metabolic diseases. The present review analyzes the gender-related differences in these pathological conditions in relation to increases in the serum levels of XOR and/or uric acid and the opportunity for gender-driven pharmacological treatment.

Keywords: cardiovascular disease; chronic kidney disease; gender medicine; gout; hypertension; metabolic syndrome; uric acid; xanthine oxidoreductase.

Figure 1

Xanthine oxidoreductase (XOR) activities and products: physiological and pathological effects. Uric acid (UA), produced by the xanthine dehydrogenase and oxidase activities of XOR, has several physiological effects: (i) regulation of blood pressure by activating the renin–angiotensin–aldosterone system, (ii) antioxidant activity, which is fundamental in biological fluids, (iii) macrophage stimulation by acting as a damage-associated molecular pattern (DAMP), (iv) fat accumulation by regulating lipidic and glycidic metabolism. However, hyperuricemia can have pathological effects, promoting hypertension and chronic inflammation, as well as inducing hypertriglyceridemia and insulin resistance. In addition, intracellular UA accumulation and UA oxidant products contribute to oxidative stress. Superoxide ion and hydrogen peroxide (ROS), produced by xanthine oxidase and reduced nicotinamide adenine dinucleotide (NADH) oxidase activities, have a redox signaling function that is essential for innate immunity because it is implicated in bactericidal action as well as cell activation, proliferation, and migration. On the other hand, excess amounts of ROS can induce endothelial dysfunction and oxidative stress. Nitric oxide (NO), produced by the nitrite reductase activity of XOR, promotes local arterial vasodilation and contributes to innate immunity by generating reactive nitrogen species (RNS). High levels of NO can induce phlogosis and tissue damage by producing cytotoxic RNS, such as peroxynitrite ion [16].

Figure 2

Uric acid (UA) and hypertension. The augmentation of circulating UA can be the consequence of genetic factors, excessive intake of fructose, purine-rich food or alcohol, or tumor lysis syndrome, as well as of a pathological decrease in renal or intestinal UA excretion. An excess amount of UA can lead to hypertension through different mechanisms. Extracellularly, the deposition of urate crystals in main vessels may trigger a proinflammatory response, thus causing direct endothelial injury and dysfunction [35]. UA can activate the renin–angiotensin–aldosterone (RAA) system by increasing the juxtaglomerular renin release. Thus, the reabsorption of sodium (Na⁺) and water (H₂O) is augmented in distal tubule, thus inducing hypervolemia. The renin release augments the formation of angiotensin 1 (Ang 1), which is converted into angiotensin 2 (Ang 2) by the endothelial angiotensin-converting enzyme (ACE). Intracellularly, UA oxidative products can cause oxidative stress and induce vasoconstriction by lowering the availability of endothelial nitric oxide (NO). Moreover, intracellular accumulation of UA induces the proliferation of smooth muscle cells, which leads to arterial stiffness by increasing the activity of mitogen-activated protein kinases (MAPK), platelet-derived growth factor (PDGF), and cyclooxygenase 2 (COX-2) [36].

Figure 3

Correlations among uricemia, gender, and age, and metabolic, cardiovascular, and renal diseases. Uricemia is lower in women than in men, with normal range values of 3.4–7.0 mg/dL for men versus 2.4–5.7 mg/dL for women. Such a difference is due, at least in part, to the uricosuric effect of estrogens, which reduce the risk of hyperuricemia in premenopausal women, thus protecting young women from hyperuricemia-related diseases. While in men, the values of uricemia slightly grow for their whole lives, in women, the level of uricemia shows a plateau during their fertility period and starts growing again after menopause. The levels of uricemia are correlated to the onset of several diseases. Hyperuricemia can cause gout and can contribute to the development of metabolic syndrome and type 2 diabetes as well as hypertension, cardiovascular disease (CVD), urate kidney stones, and chronic kidney diseases (CKD).