Aristolochic Acid I Metabolism in the Isolated Perfused Rat Kidney

Abstract

Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I and their glucuronide and sulfate conjugates that can be found in urine and faeces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urines using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate whereas the conjugated metabolites are almost exclusively secreted to the urine.

Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

“…With respect to the dosage required to elicit tubular damage, rats are the least sensitive rodent species (21). This has been attributed, in part, to the proficiency of isolated rat kidneys perfused with AA-I in producing the primary detoxication products of AA-I, namely, AA-Ia and its O6-conjugates (25). Murine kidneys lack this detoxication pathway.…”

Acute kidney injury induced by aristolochic acid in patients with primary glomerular nephritis

“…Recently, Priestap and his colleagues investigated the metabolism process of AA-I in the isolated perfusing rat kidney. 4 They found that AA-I distributed rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. And, the filtered AA-I was reabsorbed at the tubules, whereas its metabolites were secreted.…”

Organomatics and organometrics: Novel platforms for long-term whole-organ culture

“…Naturally, an isolated organ is the sole contributor to changes in metabolite concentrations, which allows these changes to be attributed to organ-specific influences. This can be exploited to study the effects of certain interventions in basic metabolic pathways 132 or the metabolism of a target compound 133,134 . Additionally, the ease of in- and outflow sampling allows for metabolic flux analysis over the organ and the evaluation of metabolic pathways over time and between groups 33,135 .…”