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Chlordecone (CD) is an organochlorine pesticide associated with albumin and high-density lipoproteins (HDL) in the plasma. It is found in higher concentrations in the liver than in other tissues and is excreted in the bile. The influence of plasma HDL on the biliary excretion of CD was studied using isolated pig liver perfused with a Krebs-Ringer bicarbonate solution containing albumin, dextrose, and pig red blood cells. Within 5 min after administration into the perfusion medium of [14C]CD bound to albumin or to HDL, only 13% of the [14C]CD dose remained in the perfusate, showing that CD is rapidly taken up by the liver. After 60 min the plasma concentration was constant at 0.008% dose/ml when [14C]CD was administered bound to albumin in the absence of HDL and at 0.004% dose/ml when administered bound to HDL. The mean concentration of CD in the bile was higher when CD was administered bound to albumin in the absence of HDL (0.039% dose/ml) than when it was administered bound to HDL (0.010% dose/ml). The elimination rate constant of CD from the liver into the bile was 0.007/min whether CD was administered bound to albumin or to HDL. The addition of HDL to the perfusion system after the administration of albumin-bound CD resulted in lower biliary CD concentrations. The results suggest that HDL affects the distribution of CD between the perfusate and liver and between liver and bile. In both cases, distribution toward the liver is favored.

The hypothesis that liver is the site of the previously demonstrated chlordecone alcohol formation in man was tested. Human bile obtained from chlordecone-poisoned factory workers contained substantial amounts of free chlordecone, but little free chlordecone alcohol. However, when the same bile specimens were pretreated with beta-glucuronidase before analysis by gas-liquid chromatography, large amounts of chlordecone alcohol appeared, accounting for 75% of total organochlorine compounds. Confirmation of the identity of chlordecone and chlordecone alcohol was made by using gas liquid chromatography-mass spectrometry. Whereas biliary chlordecone alcohol was present predominantly as its glucuronide conjugate (93%), chlordecone was excreted primarily as the unaltered compound (72%) with only a small portion conjugated with glucuronic acid (9%). The remaining fraction of the total chlordecone measured in bile appeared to be a stable polar metabolite resistant to beta-glucuronidase. This unidentified metabolite could be converted to free chlordecone only by acid hydrolysis under harsh conditions. In contrast to human bile, rat bile contained only trace amounts of chlordecone alcohol (less than 0.5% of total chlordecone), thus indicating that hepatic metabolism of chlordecone is species-specific. We conclude that in man, the major metabolic route for chlordecone is its reduction in the liver followed by glucuronidation.

Workers exposed to chlordecone (Kepone), a toxic organochlorine pesticide, excreted larger amounts of chlordecone in bile than in stool, suggesting that it may undergo enterohepatic recirculation. We found in a single subject that equal amounts of chlordecone and of its reduced metabolite, chlordecone alcohol, were excreted in bile at a rate four times as great as in stool. When biliary contents were diverted from the intestine through a T tube, fecal excretion of chlordecone alcohol was abolished, presumably due to interruption of its passage via bile to intestine. This change was not accompanied by disappearance of chlordecone from the stool. The amount of chlordecone in stool when bile was diverted was increased six- to tenfold over that when diverted bile was continuously infused into the duodenum. Analogous experiments with [14C]-chlordecone-treated rats in which bile flow was exteriorized through a plastic cannula showed that the excretion of radioactivity in feces was in the same range when bile was reinfused in the duodenum or was totally diverted. Moreover, in rats with bile diverted, cholestyramine, an anion-exchange resin which binds chlordecone in vitro, doubled the excretion of radioactivity in stool. A similar effect was observed in intact animals. We conclude that chlordecone enters the intestinal lumen from a nonbiliary source, probably the gut, and that net excretion of chlordecone from this source can be augmented by cholestyramine.