Induction of hepatic microsomal enzymes by herban®, diuron, and other substituted urea herbicides

doi:10.1016/0041-008X(70)90198-5

Toxicology and Applied Pharmacology

Volume 17, Issue 2, September 1970, Pages 406-417

https://doi.org/10.1016/0041-008X(70)90198-5 Get rights and content

Abstract

1-[5-(3a,4,5,6,7,7a-hexahydro-4,7-methanoindanyl)]-3,3-dimethylurea (Herban^®) and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron) were administered to adult female rats to determine their enzyme-inducing capacity. After determining that these compounds have the ability to increase the activity of hepatic microsomal enzymes, they were fed to male and female weanling rats in the diet at levels of 100, 250, 500, 1000, and 2000 ppm. Dose-related increases in the activities of three hepatic microsomal enzymes were observed with maximal induction occurring during the first 3 weeks of feeding. All induced enzyme activities decreased during the duration of the 13-week study except for O-demethylase activity. A sex difference was observed in the response of the animals. Males were more susceptible than female rats to the enzyme-inducing activity of these two compounds. Other urea compounds were fed to weanling and adult female rats for 1 week at a dietary level of 1000 ppm. It was found that all the herbicidal urea derivatives that were used caused induction of at least one enzyme system.

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Citation Excerpt :
Unchanged diuron also was not detected in human urine after a case of product abuse (Boven et al., 1990). Male Wistar rats developed a higher incidence of tumors compared to female rats (USEPA, 2003), and some studies showed that diuron metabolism between male and female rats was different (APVMA, 2011; Kinoshita and DuBois, 1970). In subacute studies via inhalation, male and female Wistar rats were exposed to diuron aerosol at 4.1, 37.4 and 268 mg/m3 5 days per week for 8 weeks (APVMA, 2011).
Diuron is carcinogenic to the rat urinary bladder at high dietary levels. The proposed mode of action (MOA) for diuron is urothelial cytotoxicity and necrosis followed by regenerative urothelial hyperplasia. Diuron-induced urothelial cytotoxicity is not due to urinary solids. Diuron is extensively metabolized, and in rats, N-(3,4-dichlorophenyl)urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl urea (2-OH-DCPU) were the predominant urinary metabolites; lesser metabolites included N-(3,4-dichlorophenyl)-3-methylurea (DCPMU) and trace levels of 3,4-dichloroaniline (DCA). In humans, DCPMU and DCPU have been found in the urine after a case of product abuse. To aid in elucidating the MOA of diuron and to evaluate the metabolites that are responsible for the diuron toxicity in the bladder epithelium, we investigated the urinary concentrations of metabolites in male Wistar rats treated with 2500 ppm of diuron, the urothelial cytotoxicity in vitro of the metabolites and their gene expression profiles. DCPU was found in rat urine at concentrations substantially greater than the in vitro IC50 and induced more gene expression alterations than the other metabolites tested. 2-OH-DCPU was present in urine at a concentration approximately half of the in vitro IC50, whereas DCPMU and DCA were present in urine at concentrations well below the IC50. For the diuron-induced MOA for the rat bladder, we suggest that DCPU is the primary metabolite responsible for the urothelial cytotoxicity with some contribution also by 2-OH-DCPU. This study supports a MOA for diuron-induced bladder effects in rats consisting of metabolism to DCPU (and 2-OH-DCPU to a lesser extent), concentration and excretion in urine, urothelial cytotoxicity, and regenerative proliferation.
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^☆: This investigation was supported by a research grant (ES-00109) from the United States Public Health Service.

^☆☆: Presented in part at the sixth annual meeting of the Society of Toxicology, Atlanta, Georgia, March 23–25, 1967.

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Induction of hepatic microsomal enzymes by herban®, diuron, and other substituted urea herbicides☆,☆☆

Abstract

Advan. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

The metabolic fate and excretion of drugs

Ann. Rev. Pharmacol.

Induction of hepatic microsomal enzymes by herban^®, diuron, and other substituted urea herbicides☆,☆☆