Ma Dou Ling

The aristolochic acids of this fruit cause a progressive hypocellular interstitial fibrosis of the renal cortex and upper tract urothelial carcinoma. The lesions are irreversible, no effective treatment for either exists, and there is no threshold dose below which the DNA adducts are not formed. Any co-administered nephrotoxin adds insult to a kidney already being scarred, and falling glomerular filtration in turn raises exposure to renally cleared drugs.

CYP1A1 and CYP1A2 sit on both sides of aristolochic acid I metabolism. Under aerobic conditions they O-demethylate it to 8-hydroxyaristolochic acid, a detoxication; under low oxygen they nitroreduce it and add to the adduct burden. Which reaction dominates in vivo was settled in rats: inducing CYP1A1 and 1A2 with Sudan I before dosing lowered aristolochic acid I DNA adducts in liver, kidney and lung by diverting the compound into O-demethylation. Blocking those enzymes should therefore push the balance the other way. Human CYP1A2 varies more than 60-fold between individuals, which is one reason exposed patients do not all develop disease.

Two Taiwanese cohorts, one hospital-based with 89 patients and one population-based with 2,921 cases and 11,684 controls, graded arsenic exposure from well water and arseniasis-related disease and measured aristolochic acid exposure by aristolactam-DNA adducts in renal cortex, A to T TP53 mutations and prescription records. Logistic regression showed the two carcinogens act additively on upper tract urothelial carcinoma risk. Aristolactam-DNA adducts were present in over 90 per cent of the hospital patients, whether or not they lived in an arsenic-endemic area.

Risk tracks cumulative aristolochic acid dose, and formulas routinely stack several sources. In a 200,000-patient sample of Taiwan National Health Insurance data covering 1997 to 2003, 78,644 patients received aristolochic-acid-containing products across 526,867 prescriptions, and about 7 per cent exceeded a cumulative 100 g of Xi Xin, Mu Tong or this fruit, Fructus Aristolochiae. Tian Xian Teng is the stem of the same two plants that supply this fruit, so prescribing both doubles a single botanical exposure without appearing to.

The honey-roasted form is the usual dispensing form of this fruit, and processing is often taken to have made it safe. Review of detoxication techniques for aristolochic-acid-containing drugs finds that honey and alkaline-salt processing are the two methods used in practice, that alkaline-salt processing removes far more of the acids because they are weak acids, and that no processing method removes them completely. Reduction is not elimination, and the carcinogenic endpoint has no threshold.

Aristolochic acid injuries have repeatedly arisen from substitution rather than from deliberate prescribing, the Belgian slimming-clinic nephropathy of 1993 being the founding example, in which Aristolochia material reached patients in place of a Stephania. Chinese herbal products may contain aristolochic acid or be adulterated with herbs suspected of containing it, and the commercial supply of this fruit itself is not what the pharmacopoeial listing implies: all 33 commercial Madouling samples collected from 12 Chinese provinces tested to Aristolochia contorta, although both A. contorta and A. debilis are official source plants.