Kenneth L. Davison

Mercapturic acid formation in the metabolism of propachlor, CDAA, and fluorodifen in the rat

Abstract When [ 14 C]F 3 -fluorodifen (2,4′-dinitro-4-trifluoromethyl diphenylether), carbonyl-[ 14 C]CDAA ( N,N -diallyl-2-chloroacetamide), and carbonyl- 14 C-propachlor (2-chloro- N -isopropylacetanilide) were fed to rats, 57 to 86% of the 14 C was excreted via the urine within 48 hr. Although very little radioactivity was excreted in the feces of CDAA-treated rats, 15–22% of the 14 C was excreted in the feces of propachlor- of fluorodifentreated rats and an average of 8% of the 14 C remained in these rats 48 hr after treatment. Oxidation of the 14 C label to [ 14 C]O 2 was not a major process in the metabolism of these herbicides. The only major radioactive metabolite present in the 24-h urine of fluorodifen-treated rats, 2-nitro-4-trifluoromethylphenyl mercapturic acid, accounted for 41% of the administered dose of 14 C. In the metabolism of CDAA, the corresponding mercapturic acid accounted for 76% of the dose; it was the only major metabolite present in the 24-h urine. In contrast, three major metabolites were detected in the 24-h urine of propachlortreated rats, and the mercapturic acid accounted for only 20% of the dose. The mercapturic acid of each herbicide was identified by mass spectrometry.

Comparative effects of p, p′-DDT and pentobarbital on hepatic microsomal enzymes in young quail, chicks and ducklings

Abstract 1. 1. Pentobarbital (PB) and DDT effects on microsomal mixed function oxidases of ducklings, quail and chicks were studied. 2. 2. DDT and PB exerted variable effects on body weight gain, liver to body weight ratio and hepatic microsomal protein concentration in the three species. 3. 3. PB did not affect the enzyme activities, while dietary DDT increased aniline hydroxylase, aminopyrine N-demethylase activities and cytochrome P-450 concentration in ducklings. In contrast, DDT inhibited aniline hydroxylase and aminopyrine N-demethylase activities in quail and suppressed aniline hydroxylase activity in chicks. 4. 4. Additional data showed that aniline hydroxylase was competitively inhibited by DDT in the chick.

Comparative metabolism and elimination of acetanilide compounds by rat

1. 14C-labelled propachlor, alachlor, butachlor, metolachlor, methoxypropachlor and some of their mercapturic acid pathway metabolites (MAP) were given to rat either by gavage or by perfusion into a renal artery. MAP metabolites were isolated from bile and urine. 2. Rat gavaged with propachlor and methoxypropachlor eliminated 14C mostly in urine, whereas rat gavaged with alachlor, butachlor and metolachlor eliminated 14C about equally divided between urine and faeces. When bile ducts were cannulated, the gavaged rat eliminated most of the 14C in bile for all compounds. The amount of 14C in bile from the propachlor-gavaged rat was less than that for the other acetanilides, with the difference being in the urine. 3. The mercapturic acid metabolites 2-methylsulphinyl-N-(1-methylhydroxyethyl)-N-phenylacetam ide and 2-methylsulphinyl-N-(1-methylmethoxyethyl)-N-phenylacetam ide were isolated from the urine and bile of the methoxypropachlor-gavaged rat. 4. Bile was the major route for 14C elimination when MAP metabolites of alachlor, butachlor and metolachlor were perfused into a renal artery. Urine was the major route for 14C elimination when MAP metabolites of propachlor and methoxypropachlor were perfused. Mercapturic acid conjugates were major metabolites in bile and urine when MAP metabolites were perfused. 5. We conclude that alkyl groups on the phenyl portion of the acetanilide causes biliary elimination to be favoured over urinary elimination.

Glutathione-mediated methylthio-turnover and sex differences in the metabolism of pentachlorothioanisole by rat.

1. Sex differences observed in the metabolism of pentachlorothioanisole in rat were due to: (1) greater excretion in urine by females, and greater biliary excretion by males; (2) formation of pentachlorophenyl mercapturic acid pathway metabolites by females; and (3) redox-cycling between methylthio and methylsulphoxyl oxidation congeners in intermediary metabolites by females. 2. Three methylthio-turnover processes are proposed in the intermediary metabolism of pentachlorothioanisole.

Evidence for the absence of cysteine S-conjugate N-acetyltransferase activity in the metabolism of propachlor, naphthalene, and dichlobanil in calves

1. The glutathione conjugate of 2-chloro-N-isopropyl[1-14C]acetanilide (14C-propachlor) was perfused through a calf kidney in situ; 23% of the dose was excreted in the perfused kidney urine as the cysteine conjugate, no mercapturic acid was detected. 2. A 5-day-old calf dosed orally with 14C-propachlor excreted 70% dose in the urine as the cysteine conjugate; no mercapturic acid was detected. Rumen microflora were established in the calf (5 weeks older) and the experiment was repeated with the same results. 3. When the same calf was dosed 1 week later with 14C-naphthalene, 99% dose was excreted in the urine, mostly as the dihydrodiol-glucuronide (34%) and the dihydrohydroxy-cysteine conjugate (47%); no mercapturate was detected. 4. A 9-day-old calf dosed orally with 2,6,-dichlorobenzo[14C]nitrile (14C-dichlobanil) excreted 67% dose in the urine as cysteine conjugates (34%), and products of cysteine conjugate beta-lyase cleavage of cysteine conjugates (30%); no mercapturates were detected. 5. Cysteine S-conjugate N-acetyltransferase activity in calf kidney and liver was about 10% of that in the corresponding rat tissues.

Effect of AT-125 on the metabolism of propachlor and the glutathione conjugates of propachlor and bromobenzene in rat

1. Dosing rats with the gamma-glutamyl-transpeptidase inhibitor AT-125 results in the excretion of free glutathione in the urine of rat: this treatment did not lead to the excretion of glutathione conjugates of orally dosed xenobiotics, neither did AT-125 increase the biliary excretion of glutathione conjugates. 2. Dosing rat with AT-125 prior to dosing with 2-chloro-N-isopropylacetanilide decreased the excretion of 2-methylsulphonylacetanilide metabolites from 23% of the dose to < 0.5%. 3. We conclude that glutathione and glutathione-xenobiotic conjugates are probably not processed in vivo by the same pathway, and that AT-125 can alter the in vivo transport of mercapturic acid pathway metabolites.