Factors influencing the intestinal absorption of hydrocarbon carcinogens

Laher, Janet Michelle (1983) Factors influencing the intestinal absorption of hydrocarbon carcinogens. Masters thesis, Memorial University of Newfoundland.

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Abstract

This study was undertaken to determine mechanisms involved in absorption of Tipophilic xenobiotics and to define factors which may alter their bioavailabilities. First examined were the in vitro partitions of 3 hydrocarbon carcinogens, 7,12-dimethylbenz(a)anthracene (DMBA), 3-methylcholanthrene and benzo(a)pyrene and one polychlorinated biphenyl compound, between an emulsified oil phase and a mixed micellar solution simulating intestinal content. Nearly identical behaviours were exhibited by the 4 hydrocarbons whose solubilization was directly dependent upon the formation of bile salt micelles. Solubilization was enhanced by increasing concentrations of bile salt, reduction of triglyceride concentration and the formation of mixed rather than pure bile salt micelles. Micelles containing long-chain fatty acid and monoglyceride were better able than medium-chain lipid mixed micelles to solubilize the hydrocarbons. The second part of the study examined intraluminal factors which might alter hydrocarbon bioavailability in vivo. Conscious, restrained rats were administered ³H-DMBA in various lipid test meals via duodenal cannulae. Subsequent biliary excretion or plasma levels of radiolabel were monitored using common bile duct or tail arterial catheters. In the absence of luminal bile, DMBA was absorbed from triglyceride vehicles to an appreciable extent. Luminal bile replacement did not influence radiolabel recovery from the medium-chain triglyceride (MCT) but dramatically enhanced it from long-chain triglycerides(LCT) whether mono- or polyunsaturated. With luminal bile present, plasma levels and biliary recovery were significantly greater from both LCTs than from the MCT carrier. In a 6. hour study period, plasma levels of radiolabel were inversely related to the volume of triolein carrier. Rats receiving intraduodenal infusions of ³H-DMBA biliary products subsequently eliminated 33% of the dose in their bile within 24 hours. In rats with lymphatic fistulae, biliary radiolabel excretion was used as an indirect index of hydrocarbon. Increasing doses of radiolabel were administered then relative lymphatic and biliary radiolabel recoveries were monitored. Despite a 2000-fold variation in dose (10 μq vs 20 mg) total recoveries as percentage administered were similar. Although some degree of increased lymphatic transport was evident with increasing DMBA burden, at least 75% of absorbed radiolabel was transported in portal blood. This study demonstrates that conditions favouring micellar solubilization of hydrocarbon in the intestinal lumen produce greatest bioavailabilities. Portal transport accounts for the major route of hydrocarbon (or derivative) transport following ingestion with the lymphatic system playing only an auxiliary role. 0nce in the body, the compound is efficiently excreted in the bile and extensive enterohepatic recycling ensues.

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