The metabolism of pentachloronitrobenzene and 2:3:4:6-tetrachloronitrobenzene and the formation of mercapturic acids in the rabbit

Abstract

In the rabbit 2:3:5:6-tetrachloronitrobenzene is metabolized by reduction of the nitro group, hydroxylation and mercapturic acid formation (Bray, Hybs, James & Thorpe, 1953). The last reaction is of particular interest since it is accompanied by loss of a nitro group directly attached to the benzene ring. Two further examples of this type of reaction were encountered when pentachloronitrobenzene and 2:3:4:6-tetrachloronitrobenzene were given to rabbits (Betts, James & Thorpe, 1953). A more detailed study of the metabolism of these two compounds is now reported. The stability of the nitro group in pentachloro-, the tetrachloro-and three trichloro-nitrobenzenes has been examined in relation to formation of mercapturic acids from the highly chlorinated nitrobenzenes. METHODS Melting points are uncorrected. Materials. Pentachloronitrobenzene, m.p. 1460, was supplied by Bayer Agriculture Ltd. and Hickson and Welch Ltd. and 2:3:5:6-tetrachloronitrobenzene, m.p. 990, by Bayer Agriculture Ltd. 2:3:4:6-Tetrachloronitrobenzene, m.p. 410, was prepared from 2:4:6-trichloroaniline, which was converted by a Sandmeyer reaction into 1:2:3:5tetrachlorobenzene; this was nitrated by refluxing for 0-5 hr. with HNO3 (sp.gr. 1-52) to give 2:3:4:6-tetrachloronitrobenzene. (Details were kindly supplied by Dr M.

Transformations of pentachlorophenol

“…The bulk of the substrate was found in the urine, only small amounts were excreted with the faeces. After Betts et al (1955) confirmed the results of Deichmann et al as PCP in the urine of rabbits was not excreted in a conjugated form, PCP seemed to be metabolically inert. After these reports no publications on the metabolism of PCP in animals appeared for the following 15 years.…”

The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

“…Compounds of this type, which are metabolized to mercapturic acids in rabbits (Table V) include mono-, di-, and trihalogenonitrobenzenes Thorpe, 1955a,b, l956,1957a, 195th). This same enzyme probably conjugates glutathione with certain tetrahalogenonitrobenzenes that are metabolized to mercapturic acids (Bray, Hybs, James, and Thorpe, 1953;Betts, James, and Thorpe, 1955) by repIace- ment of nitro groups (Al-Kassab et al, 1963). The nitro group is also lost during mercapturic acid biosynthesis from certain trihalogenonitrobenzenes and from pentahalogenonitrobenzene (Betts, James, and Thorpe, 1955;Betts, Bray, James, and Thorpe, 1957), and it appears that the nitro group is lost where it is flanked by halogen atoms and there is another halogen atom in the ring, viz., k and 7.…”

“…This same enzyme probably conjugates glutathione with certain tetrahalogenonitrobenzenes that are metabolized to mercapturic acids (Bray, Hybs, James, and Thorpe, 1953;Betts, James, and Thorpe, 1955) by repIace- ment of nitro groups (Al-Kassab et al, 1963). The nitro group is also lost during mercapturic acid biosynthesis from certain trihalogenonitrobenzenes and from pentahalogenonitrobenzene (Betts, James, and Thorpe, 1955;Betts, Bray, James, and Thorpe, 1957), and it appears that the nitro group is lost where it is flanked by halogen atoms and there is another halogen atom in the ring, viz., k and 7. With 1,3-dichloro-2-nitrobenzene (8), however, although the nitro group has two neighboring halogen atoms, an additional halogen atom is not present in the ring and no mercapturic acid is formed (Bray, James, and Thorpe, 1957b).…”

“…In other cases, the halogen atom ortho to the nitro group is however, no mercapturic acid formation has been observed from dihalogenonitrobenzenes containing groups adjacent or symmetrical in position (Bray et al,l957h), and the major metabolites are dichloroanilines and glucuronic and sulfuric acid conjugates of phenols. The stability of the nitro group of some polyhalogenonitrobenzenes has been compared with the extent of mercapturic acid formation; increased lability of the respective halogen or nitro group during alkaline hydrolysis in vitro was related to increased mercapturic acid formation in vivo (Betts, James, and Thorpe, 1955;Bray et al, 1957a). Examination of the tumor initiatory activity of pentachloronitrobenzene and three tetrachloronitrobenzenes on mouse skin (Searle, 1966) showed that the compound with a stable nitro group, 1,2,3,4-tetrachloro-6-nitrobenzene, was the most potent.…”

Effect of Glucosamine on Urinary Excretion of Salicylate

“…In a number of other studies where sulfates, glucuronide ethers, and glycine conjugates have been formed as drug metabolites, it has been found that the rate of their elimination was greater than the rate of their formation (11)(12)(13)(14). Although this assumption must be employed cautiously, it appears to have validity in this particular study.…”