Potential benefits of quinoxaline 1, 4-dioxides in aldosterone dysmetabolism disease—A medical hypothesis

doi:10.4236/ojas.2011.13016

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Vol.1, No.3, 121-127 (201

doi:10.4236/ojas.2011.13016

1) Op en Journal of Anim al Sciences

Potential benefits of quinoxaline 1, 4-dioxides in

aldosterone dysmetabolism disease

—A medical hypothesis

Da-Jiang Zou1, Qiao-Feng Zheng1, Xian-Ju Huang1,*, Xu Wang2, Awais Ihsan2

1College of Pharmacy, South-Central University for Nationalities, Wuhan, China; *Corresponding Author:

huangxianju1972@yahoo.cn

2National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory of Food Safety Evaluation, Huazhong Agri-

culture University, Wuhan, China.

Received 13 June 2011; revised 20 July 2011; accepted 22 August 2011.

ABSTRACT

Quinoxaline 1, 4-dioxides (QdNOs) are quinoxa-

line derivatives which have been used as an-

timicrobial agents and growth promoters in

animals widely. They are also assumed to cure

human disease such as anticancer, antituber-

cular and inhibiting parasite. QdNOs such as

carbadox and their major metabolites induced a

special decline of aldosterone production from

the swine adrenal in vivo and in vitro, and thus

cause hypovolemia, hyponatremia and hyper-

kalemia. This can also be expected to be the

case for human. As a mainly physiological

hormone and a novel steroid w ith potent miner-

alocorticoid activity, aldosterone plays an im-

portant role in the pathophysiological process

of brain, renal and heart disease progression

and may be a renal and vascular risk factor.

Here, we provide evidence to support the hy-

pothesis that QdNOs may lead potential benefit s

in aldosterone dysmetabolism disease via the

synthesis deficiency of aldosterone in adrenal

and/or the cardiovascular tissues. If the hy-

pothesis is true, it may provide a new option

into the therapy for aldosterone dysmetabolism

disease, especially in cardiovascular system,

and thus assume a broader application of

QdNOs.

Keywords: Quinoxaline 1; 4-Dioxides; Aldosterone;

Adrenal Gland; Dysmetabolism; Cardiovascular

Tissues

1. INTRODUCTION

Since 1940s, Quinoxaline-di-N-oxides (QdNOs) (Fig-

ure 1) are known as potent antibacterial agents which act

on several gram-positive and -negative species [1-4]. For

this reason they have been used as growth promoters in

agricultural stock farming to promote growth of pigs,

cattle, fish and poultry when added to the feed during

rearing in dosages 25 - 100 mg/kg [5-8].

Recently, extensive study has been carried out on

QdNOs which indicates that they can be also applied for

treatment of human diseases. For example, QdNOs have

shown a selective cytotoxicity against hypoxic cells pre-

sented in solid tumors [9-11]. It was [12] demonstrated a

dose-dependent inhibition of the proliferation of T-84

human colon cancer cells by QdNOs. Other studies have

put in evidence that QdNOs are endowed with antitu-

bercular activities in vitro. They have inhibitor activity

of clinical isolates of Mycobacterium tuberculosis [13]

or Mycobacterium tuberculosis H37Rv [14-15]. Fur-

thermore, QdNOs presented good in vitro inhibitor ac-

tivity of Trypanosoma cruzi, the causative agent of Cha-

gas’ disease affects around 20 million people in Central

and South America [16].

The endocrinological effects of these compounds have

long been recognized. Besides their influence on meta-

bolic hormones and epidermal growth factor in swine

[17] QdNOs such as carbadox and its major metabolites

induced a special decline of aldosterone production from

the adrenal in vivo and in vitro, and thus cause hypo-

volemia, hyponatremia and hyperkalemia [18-21] Al-

dosterone is a steroid hormone and the most important

mineralocorticoid in the human body. Clinically, excess

aldosterone is associated with increased stroke risk [22];

progressive renal disease [23], higher morbidity and

mortality in cardiovascular diseases such as myocardial

infarction (MI) and heart failure (HF) [24-25]. Here, we

provide evidence to support the hypothesis that QdNOs

can lead potential benefits in cardiovascular or other

diseases caused by metabolism dysfunction of aldoster-

on via the synthesis deficiency of aldosterone. e

D.-J. Zou et al. / Open Journal of Animal Sciences 1 (2011) 121-127

122

Figure 1. Chemical structures of some quinoxaline 1, 4-oxides.

2. DETAILS AND ANALYSIS

2.1. Metabolic Pathway of Aldosterone

Biosynthesis

Induction of aldosterone biosynthesis can be divided

into two temporal phases: an acute phase resulting from

accelerated cholesterol translocation and a chronic phase

involving synthesis of mRNA and enzymes [26]. There

are four enzymes involved, i.e. Cholesterol desmolase

(CYP11A), 21-hydroxylase (CYP21), 3β-Hydroxysteroid

dehydrogenase (3β-HSD) and aldosterone synthase

(CYP11B2). CYP11A, CYP21 and CYP11B2 are cyto-

chromes P450 (CYP), membrane-bound heme-containing

enzymes that accept electrons from NADPH via acces-

sory proteins and utilize molecular oxygen to perform

hydroxylations or other oxidative conversions. 3β-HSD

is a member of the short-chain dehydrogenase family

[27-28]. Biosynthetic reactions of aldosterone happened

not only in adrenal but also in other tissues. CYP11B2 is

expressed both in the zona glomerulosa and ex-

tra-adrenal tissues. Such synthesis has also been detected

in brain [29-30], heart [31-32] and vascular smooth

muscle [33-34]. Perfusion of angiotensin II increased

local aldosterone production, suggesting that aldosterone

is formed within the isolated tissue from a locally pre-

sent substrate [35]. Even though the function of

CYP11B2 in most of the tissue is not fully understood,

aldosterone synthesized in these tissues can elicit impor-

tant biological responses in an autocrine or paracrine

fashion.

Disorder of aldosterone biosynthesis can lead to ster-

oid hormone-related diseases such as hypoaldosteronism

and hyperaldosteronism. Defective aldosterone biosyn-

thesis may be caused by congenital adrenal hyperplasia

due to CYP21 deficiency, in which case cortisol biosyn-

thesis is also affected, or as an isolated defect termed

CYP11B2 deficiency [27]. Primary hyperaldosteronism

is a state characterized by long-standing aldosterone

excess and suppressed plasma renin activity, resulting in

hypertension and hypokalemia. It is the most common

endocrine cause of hypertension and affects 5% - 13% of

all patients and is commonly caused by aldosterone-pro-

ducing adenoma (APA) or bilateral idiopathic hyperal-

dosteronism [36-37] (IHA).

2.2. Deleterious Effects of High Levels of

Aldosterone

As a mainly physiological hormone and a novel ster-

oid with potent mineral corticoid activity, aldosterone

controls electrolyte balance, plasma volume, and vascu-

lar functions. With a low salt intake plasma aldosterone

concentration may increase to high levels without any

negative effects on the organism. However, growing

body of evidence suggests that high plasma aldosterone

levels have been shown to correlate with hypertension

[38], left ventricular hypertrophy [39-41], stroke [22]

and renal dysfunction [23]. Genetic and experimental

models of hypertension have demonstrated that excess

aldosterone induces severe injury in the heart, brain and

kidneys [23]. Aldosterone synthesis in the cardiovascular

system is up regulated during both acute MI and the as-

sociated remodeling of the myocardium [42], an effect

D.-J. Zou et al. / Open Journal of Animal Sciences 1 (2011) 121-127

123

that is believed to be due to local angiotensin II produc-

tion [43], suggesting that tissue-specific effects of al-

dosterone contribute to pathophysiological changes.

The neurohormonal actions of aldosterone influence

the prognosis of patients with HF and ischemic heart

disease through two main electrolyte homeostatic actions.

Firstly, overproduction of aldosterone leads to inappro-

priate levels of sodium and water retention, which sets

up a vicious cycle whereby the kidney attempts to com-

pensate for impaired cardiac output by releasing angio-

tensin II, leading to further rises in aldosterone and

volume overload. Secondly, aldosterone increases the

urinary excretion of magnesium and potassium leading

to electrolyte imbalance, increasing the risks of ven-

tricular arrhythmias—which in the presence of myocar-

dial remodelling following MI or secondary to HF, in-

creases risk of sudden death [44]. In several pathological

conditions aldosterone promotes vascular damage by

formation of reactive oxygen species [45]. Moreover,

clinical and experimental data indicate that aldosterone

and its receptor are implicated in various non-renal loca-

tions [41], in particular the heart [35], brain tissue [46],

and within the vasculature [47], suggesting that aldos-

terone also exerts local effects in tissue levels.

Aldosterone exerts most of its biological effects on

cells by occupying an intracellular receptor, termed the

type I or mineralocorticoid receptor (MR), which then

binds DNA and thereby influences transcription of vari-

ous genes [38-49]. However, not all of the actions of

aldosterone are mediated by the classic genomic path-

way involving transcription and translation. There is

experimental evidence that aldosterone in a number of

circumstances can stimulate an increase in intracellular

calcium concentration and cause vasoconstriction by a

mechanism which involves protein kinase C (PKC), and

which may be independent of the classical MR. Despite

pharmacological antagonism of aldosterone, which is

nowadays part of a commonly applied standard therapy,

could markedly reduce myocardial injury, cerebral hem-

orrhage and renal vascular disease, most of the

non-classical effects are insensitive to inhibitors of the

classical cytosolic mineralocorticoid receptor [50].

Moreover, this type of chemical also has some adverse

effect such as breast tenderness with or without gyneco-

mastia. It occurs more commonly in men but not exclu-

sively. Studies indicate that approximately 10% of men

will complain of breast tenderness with use spironolac-

tone at the 25 mg dose. Other adverse effects that are

associated with spironolactone include sexual dysfunc-

tion and menstrual irregularities [51].

2.3. Evidences of Quinoxaline 1, 4-Dioxides

in Aldosterone Production

Experimental studies in pigs fed with carbadox,

olaquindox, and cyadox had revealed obvious decreases

in aldosterone and sodium concentrations in blood, with

increases in potassium levels at 150 mg/kg or above

[52-53]. As these drugs are given continuously, the bio-

genesis of aldosterone in vivo is likely to be seriously

impaired, even when used in the advised dosages. Pigs

treated with 100 and 200 mg/kg carbadox showed a sig-

nificant decline of aldosterone after five and three weeks,

respectively. With olaquindox a continuous, significant

decline was found from 50 mg/kg and above after five

weeks. In the cyadox groups, a significant decline was

measured after six weeks in the 50, 200 and 400 mg/kg

groups [52]. The animals might compensate with en-

hanced production via the alternative pathway and/or by

enhanced release of other corticosteroids with mineralo-

corticosteroid activity. The rapid shutdown of the mito-

chondrial biogenesis of corticosteroids by QdNOs will

then lead to hypoaldosteronism [51,54]. Moreover, the

aldosterone decline effect was also seen in vitro. Spier-

enburg et al. investigated that the carbadox had the abil-

ity to inhibition of aldosterone production by pig adrenal

slices. A dose dependent decrease in aldosterone produc-

tion was reported at the 1~40 µg/ml [55]. In a study us-

ing a suspension of porcine adrenocortical cells, QdNOs

were found to reduce the output of aldosterone. The car-

badox and their major metabolites induced a slowly de-

veloping but virtually irreversible inhibition of the C18

transformations from corticosterone to aldosterone. But

these compounds hardly affected the alternative pathway

from deoxycortisol [17-18].

Obviously, the information obtained above is rather

insufficient to interpret the mechanisms of QdNOs on

aldosterone production related gene expression and en-

zymes interactions. More detailed investigation is re-

quired to delineate the pathophysiological linkage

among QdNOs exposure, aldosterone synthesis, and

aldosterone dysmetabolism diseases. Recently, our pre-

vious work in vivo [56-57] and in vitro [57] have sug-

gested that high dose of QdNOs could lead to adrnal

gland impaiment and aldosterone down-regulation,

combined with sodium decrease and potassium increase

in rat plasma. It’s demonstrated that a complex crosstalk

between ROS-generating system and aldosterone secre-

tion. The induction of oxidative stress following expo-

sure to mequindox (MEQ) could result in a membrane

damage and dysfunction of adrenal mitochondrion, and

then cause the contents loss of steroid hormone includ-

ing CYP11A1, CYP11B1 and CYP11B2, finally leading

to the deregulation of steroid hormone secretion and

unbalance of ion concentration [55]. Moreover, Higher

doses of MEQ showed similar depressive responsibility

for most of renin-angiotensin-aldosterone system

D.-J. Zou et al. / Open Journal of Animal Sciences 1 (2011) 121-127

124

(RAAS) components in adrenal and kidney, indicating a

down-regulation of both intra- and extra-RAAS, the up-

stream of aldosterone production [58].

2.4. Nucleotide Similarity of Aldosterone

Biosynthesis Enzymes in Human and

Pig

Although exposure to QdNOs would lead to deregula-

tion of aldosterone production in pigs, little information

is known regarding their influence on human body. To

evaluate the potential role of QdNOs in human aldos-

terone production, a multiple sequence alignment of the

full length nucleotide sequence of CYP11A (GeneID: Sus

scrofa 403329; Homo sapiens 1583), CYP21 (GeneID:

Sus scrofa 403337; Homo sapiens 1589)and 3β-HSD

(GeneID: Sus scrofa 445539; Homo sapiens 3284) gene

were identified by performing BLASTN searches in

GenBankTM. Sus scrofa and Homo sapiens shared 84%

identity with CYP11A1, 84% identity with CYP21A and

79% identity with 3β-HSD, respectively. The great simi-

larity of aldosterone biosynthesis enzymes between hu-

man and pig confirmed the possibility that QdNOs in-

fluence aldosterone synthesis enzymes in human body.

As QdNOs and their major metabolites induced a special

decline of aldosterone production from the swine adrenal

in vivo and in vitro, this can also be expected to be the

case for human.

3. DISCUSSION

Based on above information, there is plenty of evi-

dence to support the notion that aldosterone is an inde-

pendent risk factor for brain, renal and heart disease.

QdNOs may be helpful for the diseases caused by ele-

vated levels of aldosterone. Thus we focus on the hy-

pothesis that QdNOs could also cause aldosterone defi-

ciency in human body and be beneficial for aldosterone

dysmetabolism disease, which may suggest a newly

candidate remedy for cerebrovascular system, renal and

cardiovascular disease.

Although treatment with a mineralocorticoid receptor

antagonist promotes blood pressure (BP) reduction and

regresses target organ damage, they may be useless for

non-genomic aldosterone action in clinical studies par-

ticularly in the cardiovascular system [49]. QdNOs have

an effect independent of MR and perhaps act on the up-

stream cascade of aldosterone production, which is to-

tally different with mineralocorticoid receptor antagonist.

Further research on QdNOs may improve the under-

standing of their participation in the pathogenesis of

aldosterone related diseases and eventually enhance the

options for therapy.

There are at least three proposed mechanisms of

QdNOs mediated in aldosterone deficiency and heart

disease. Firstly, we postulate that the mechanism by

which QdNOs inhibit the production of aldosterone,

mainly by regulating some key enzymes necessary for

aldosterone biosynthesis. To make known whether it is

true, interaction of QdNOs with aldosterone associated

physiological regulators, enzymes and cellular second

messengers should be investigate to further discuss their

mechanisms. Secondly, as most of enzymes involved in

the biogenesis of adrenal steroids are also present in

other steroid hormone producing organs, aldosterone

produced within brain or heart was suggested to be

similarly influenced by QdNOs. A comparable differen-

tial effect of QdNOs on the biogenesis and release of

steroid hormones is to be expected. Lastly and most im-

portantly, the chronic and continuously down regulation

of aldosterone level in plasma and/or heart tissue caused

by QdNOs would lead a directly shutdown of MR affini-

ties, which may be an important direction in the therapy

for heart diseases. Future pre-clinical and clinical studies

associated with the precise mechanisms for QdNOs on

heart diseases are anticipated. These studies should cir-

cumvent (1) appropriate pathological models in vivo and

in vitro, (2) secure evaluation of QdNOs for their toxic-

ity and adverse effects on human or other animals, (3)

comparison between QdNOs and aldosterone antagonists

such as eplerenone，K+-canrenoate or spironolactone, the

agents being currently used clinically [59]. All of the

above hypothesis are testable in lab or in clinical.

Although QdNOs are known to their adrenal or other

toxicities [19,21,60], their adverse effects can be avoided

or decreased by controlling the dose. This aldosterone

inhibition effect of QdNOs occurs in concentrations well

below toxicity concentration found in vivo treatment.

Moreover, some QdNOs such as cyadox is relatively less

toxic and effective member of this family. Cyadox has

been shown to be a very safe drug when used as a feed

additive, and thus should be taken more attention than

others.

4. CONCLUSIONS

It is meaningful to investigate the profitable role of

QdNOs in cardiovascular or other diseases caused by

metabolism dysfunction of aldosterone, which will lead

to a further study in this kind of chemical. If the hy-

pothesis is true, it may provide a new option into the

therapy for aldosterone dysmetabolism disease, espe-

cially in cardiovascular system, and thus assume a

broader application of QdNOs.

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