Variability of Sulfotransferase Activity in Humans: an Approach to Improve Predictive Drug Response Part II: Analysis of Interindividual Variation in Hypertensive Patients

Current approaches to the personalization of hypertension treatment focus primarily on genome sequences and several recent studies have provided insights into the genetic regulation of hypertension. Genome sequences alone, however, do not account for environmental and lifestyle factors that also contribute to hypertension and other common and complex cardiovascular and renal diseases. (Kotchen et al. 2016) The field of hypertension needs clinically applicable phenotyping methods permitting inferences about pathophysiology and expected treatment response.

SULT are at the crossroad of metabolic pathways of catecholamines, drugs including antihypertensives and diverse environmental xenobiotics. Furthermore, SULT display wide interindividual variability, accounted for by ethnically distributed genetic variation (SNPs and CNV), regulation by nuclear receptors, PAPS availability and inhibition by various drugs and environmental compounds.(Marto et al. 2017) We hypothesize that sulfonation varies between hypertensive subjects and low sulfonation phenotypes could be related to deficient inactivation of catecholamines, influencing the pathophysiology of hypertension. We also anticipate that the sulfonation phenotype of an individual could determine response to certain antihypertensive drugs, whether because they are substrates of SULT, inhibitors of SULT or because they interfere with catecholamine activity (adrenergic blockers).

In our current study, we will study the interindividual variation of sulfoconjugation in patients with hypertension. We will quantify SULT activity using the index of sulfonation we previously described (Marto et al. unpublished), built with the mass spectrometry urinary metabolites of paracetamol, our probe substrate. We will look for associations between patients' characteristics and sulfonation phenotype and for differences in SULT activity in subgroups of patients, defined according to concurrent comorbidities and therapeutic regimen.

We expect to find individuals at the extremes of sulfonation phenotype (high and low sulfonators), with low sulfonators having more severe forms of hypertension, requiring a higher number of antihypertensive drugs.(Williams et al. 2018) If confirmed, management of hypertension in this subpopulation of patients could include induction of SULT activity or avoidal of SULT inhibitors.

Accordingly, our purpose is to explore the clinical significance of the variation of SULT activity in hypertensive patients, as an emergent blood pressure and drug response determinant.

This is an exploratory, open-label, nonrandomized clinical trial, spanning over a 6-month period, to assess interindividual variation of SULT activity in patients with arterial hypertension. Subjects must be consenting adults with a diagnosis of arterial hypertension, who comply with the inclusion and exclusion criteria listed below. Patients will be screened at visit 1, and if they meet the inclusion/exclusion criteria they will receive the intervention at visit 2. Baseline blood and urine samples will be collected.

At visit 2, complying subjects will receive a tablet containing 1 gram of paracetamol and have blood and urine samples collected 2 hours after administration. The subjects will come for 3 visits during the study. Visits 1 and 2 must occur from within 0 to 7 days of each other and visit 3 will be scheduled four weeks (± 3 days) after visit 2.

Study visits 1 and 2 will take place at Hospital da Luz in Lisbon, Portugal, and study visit 3 will follow through telephone contact.

The study population will include adult patients with arterial hypertension who will be recruited from the Internal Medicine inpatient and outpatient clinic at Hospital da Luz. Recruitment will continue until 73 patients are included.

Paracetamol and its metabolites will be quantified in plasma and urine samples using liquid chromatography mass spectrometry.