Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins.

Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.

Leaf-air transfer of organochlorine pesticides from three selected vegetables.

The leaf-air transfer of organochlorine pesticides (OCPs) in three kinds of vegetables, namely lettuce, romaine and garlic leaves was investigated. It was found that although the uptake of OCPs by the three selected vegetables was similar under controlled conditions, the depuration varied significantly among chemicals and plant species in terms of elimination rate, final residue of each OCPs, as well as the effect of temperature on the residue of OCPs in the vegetables. The results indicated that neither QCB nor HCB could be trapped tightly by any of the three selected vegetables, in contrast, p,p'-DDT could be retained effectively by all of them; the retainment of alpha-HCH, gamma-HCH, p,p'-DDE, was dependent on the vegetable species, of which the garlic leaf had the biggest ability to trap them. Our work provided insight into the behavior of OCPs in the agroecosystem.

Fish oil enhances pentachlorobenzene metabolism and reduces its accumulation in rats.

To investigate the influence of dietary fats on the metabolism and excretion of pentachlorobenzene (PECB), rats were fed semipurified diets containing soybean oil, lard or fish oil (10 g/100 g diet) for 2 wk. Rats then received a single dose of PECB by intragastric gavage. Blood concentration of pentachlorophenol (PCP), a major metabolite of PECB, was higher after 5 h through d 3 and that of PECB was lower after d 5 in the rats fed fish oil than in rats fed the other fats. After d 5, the highest ratio of PCP/PECB in the liver was seen in the fish oil-fed rats. Furthermore, fish oil intake resulted in a markedly lower concentration of PECB in fat tissues, where a large amount of PECB is typically distributed due to its lipophilic property. These findings indicate that fish oil feeding enhances PECB metabolism, thereby decreasing PECB residues in the body. Fish oil-fed rats had a smaller epididymal fat tissue mass compared with lard- or soybean oil-fed rats. The small mass of the fat tissues apparently limited the accumulation of PECB in those tissues and thus accelerated PECB metabolism in the liver.

Effect of dietary protein and sulfur-containing amino acids on urinary metabolites in rats injected with chlorobenzene.

Rats were fed for 10 days a 10 or 20% casein diet, or the diets with 0.3% DL-methionine or L-cystine. Rats fed the 20% casein exceeded those fed the 10% casein in growth, hepatic glutathione (GSH) levels, and microsomal drug-metabolizing activities including cytochrome P-450, aminopyrine N-demethylase, and aniline hydroxylase. Supplement with methionine or cystine had significantly elevated hepatic GSH, regardless of the casein content. After the feeding, rats were intraperitoneally injected with chlorobenzene (0.5 mmol/kg body weight), and the urinary metabolites (4-chlorophenylmercapturic acid (4-CPMA), 2-, 3- and 4-chlorophenol (CPs), 4-chlorocatechol (4-CC), and 2-, 3- and 4-chlorophenylmethylsulfide (CPMSs) ) were measured for 24 hours post-injection. Rats fed the 20% casein exceeded those fed the 10% casein in 4-CPMA, CPs, and in total urinary metabolites. Supplement with methionine or cystine to the 10% casein significantly increased 4-CPMA and decreased 4-CC. Supplement with methionine or cystine to the 20% casein also significantly increased 4-CPMA excretion, but had no effect on urinary 4-CC. The highest urinary excretion of CPMSs was observed in rats fed the 10% casein. Both increase of dietary protein and addition of the sulfur-containing amino acids decreased urinary CPMSs. These results indicate that total urinary metabolites are strongly associated with the microsomal drug-metabolizing activity, formation of the mercapturic acid is dependent on the hepatic GSH level, and the urinary CPMS level is independent on the mercapturic acid formation.

The role of oxidative metabolism in hexachlorobenzene-induced porphyria and thyroid hormone homeostasis: a comparison with pentachlorobenzene in a 13-week feeding study.

Hexachlorobenzene (HCB) induces a broad spectrum of effects including disturbances in the heme synthesis (porphyria) and in thyroid hormone homeostasis. For most of its effects, biotransformation of the parent compound seems to be a prerequisite. The present study was designed to assess the relevance of the oxidative metabolites in HCB-induced toxicity, with special attention to the role of the reactive tetrachlorobenzoquinone (TCBQ). To this end, toxicity and biotransformation of HCB were compared with those of pentachlorobenzene (PCB), since this chemical is oxidized to the same products as HCB, i.e., pentachlorophenol (PCP) and TCBQ. Female Wistar rats received diets containing different dose levels of HCB or PCB for 13 weeks, with or without cotreatment with triacetyloleandomycin (TAO), a selective inhibitor of cytochrome P450IIIA1/2. Rats treated with HCB (high dose) had significantly elevated levels of urinary porphyrins from the 4th week on and had a significant hepatic accumulation of porphyrins at the end of the study. Both urinary porphyrin excretion and hepatic porphyrin accumulation were greatly inhibited in rats receiving cotreatment with HCB and TAO. However, the inhibition of HCB-induced porphyria by TAO cannot be explained by a diminished formation of the highly reactive TCBQ, since rats treated with a high dose of PCB, which had a several fold higher urinary excretion of PCP and TCHQ compared to a high dose of HCB, did not develop porphyria. Instead, the present study points to the involvement of a putative reactive intermediate in the primary oxidative step in HCB-induced porphyria, since based on paired observations of individual rats, the degree of porphyria was correlated to a high degree with excretion of PCP, whereas correlation of porphyria with early excretion of TCHQ was much weaker. This finding fits well with the fact that the mechanisms of oxidation of HCB to PCP and PCB to PCP are different. Both HCB and PCB were oxidized to PCP and tetrachlorohydroquinone (TCHQ), the reduced analog of TCBQ. Cytochrome P450IIIA1/2 appears to be involved in the conversion of HCB and PCB, since cotreatment of TAO resulted in a strongly diminished urinary excretion of PCP and TCHQ. Treatment with HCB as well as PCB results in disturbances of retinoid and thyroid hormone homeostasis. These effects, which have also been reported after exposure to polychlorinated biphenyls, originate from interference of hydroxylated metabolites (notably PCP) with the plasma thyroxine transport protein, transthyretine, and since this metabolite is formed from both HCB and PCB, this results in the same toxicity for both compounds.