Hydroquinone toxicity

Rates of hydroquinone glucuronidation in human liver microsomes showed a two- to three-fold variation between individual liver samples they were somewhat higher than in the rat, and lower than in the mouse liver (Seaton et al., 1995). A compartmental pharmacokinetic model was derived to describe the pharmacokinetics of hydroquinone in vivo in humans, rats and mice, incorporating hydroquinone glucuronidation rates sulfation of hydroquinone was not included in this model. NAD(P)H quinone acceptor oxidoreductases protect against reactive quinones by reducing them to the hydroquinone this enzyme seems to be absent in some individuals, which will lead to loss of such protection and make them more sensitive to hydroquinone toxicity (Ross, 1996). 

Acrolein is a highly toxic material with extreme lacrimatory properties. At room temperature acrolein is a Hquid with volatiUty and flammabiUty somewhat similar to acetone but unlike acetone, its solubiUty in water is limited. Commercially, acrolein is always stored with hydroquinone and acetic acid as inhibitors. Special care in handling is required because of the flammabiUty, reactivity, and toxicity of acrolein. 

Neither the mechanism by which benzene damages bone marrow nor its role in the leukemia process are well understood. It is generally beheved that the toxic factor(s) is a metaboHte of benzene (107). Benzene is oxidized in the fiver to phenol [108-95-2] as the primary metabolite with hydroquinone [123-31-9] catechol [120-80-9] muconic acid [505-70-4] and 1,2,4-trihydroxybenzene [533-73-3] as significant secondary metabolites (108). Although the identity of the actual toxic metabolite or combination of metabolites responsible for the hematological abnormalities is not known, evidence suggests that benzene oxide, hydroquinone, benzoquinone, or muconic acid derivatives are possibly the ultimate carcinogenic species (96,103,107—112). 

Distil rapidly through an efficient 25cm column after adding 0.5g of hydroquinone/200g of chloride, and then redistil carefully at atmospheric pressure preferably in a stream of dry N2. [J Am Chem Soc 72 72, 2299 1950.] The liquid is an irritant and is TOXIC. 

Methylparathion is the corresponding dimethyl derivative. Later (1952) malathion found favour because of its decreased toxicity to mammals it is readily made in 90% yield by the addition of dimethyidithiophosphate to diethylmaleate in the presence of NEtr as a cataly.st and hydroquinone as a polymerization inhibitor ... 

Whereas photolysis of 2- and 4-chlorophenols in aqueous solution produced catechol and hydroquinone, in ice the more toxic dimeric chlorinated dihydroxybiphenyls were formed (Blaha et al. 2004). 

The tolerance of the strains to high concentrations of pentachlorophenol—S. chlorophenolica appears to be less sensitive than M. chlorophenolicus (Miethling and Karlson 1996). This may be attribnted to the ability of the cells to adapt their metabolism to avoid synthesis of toxic concentrations of chlorinated hydroquinones, and is consistent with the low levels of these metabolites measnred in the cytoplasm of cells metabolizing pentachlorophenol (McCarthy et al. 1997). Inocnla have also been immobilized on polyurethane that, in addition, ameliorates the toxicity of chlorophenols (Valo et al. 1990). 

The toxicity of 3-methylindole has been attributed to methyleneindolenine trapping of nitrogen and sulfur nucleophiles.57 60-62 Likewise, the ene-imine shown in Scheme 7.9 readily reacted with hydroquinone nucleophiles, resulting in head-to-tail products. Shown in Fig. 7.6 is the 13C-NMR spectrum of a 13C-labeled ene-imine generated by reductive activation. The presence of the methylene center of the ene-imine is apparent at 98 ppm, along with starting material at 58 ppm and an internal redox reaction product at 18 ppm. Thus, the reactive ene-imine actually builds up in solution and can be used as a synthetic reagent. 

At the Sn02 anode only a very small amount of highly toxic intermediates (hydroquinone, catechol, benzoquinone) is formed. These intermediates are formed in large amounts on the Pt anode probably by chemical reaction of adsorbed hydroxyl radicals with phenol. 

Although reduction of quinones is usually a detoxication pathway, there are examples such as mitomycin C in which the hydroquinone is more toxic than the quinone as shown in Figure 5.12 and this may increase the susceptibility of cancers that express high levels of NQO. In this case, the reduction of the quinone leads to the loss of methanol, which is the first step in the activation of this anticancer agent (20). 

A large number of studies have investigated the metabolism of benzene per se or in relation to toxification and, particularly, myelotoxicity. Most evidence shows that benzene oxide (10.1, Fig. 10.8) is not the ultimate toxic species, as was initially believed. Indeed, phenol and quinone metabolites of benzene are more active in forming adducts with macromolecular nucleophiles and eliciting cellular toxicity. For example, the efficacy of benzene metabolites (see Fig. 10.8) to inhibit DNA synthesis in a mouse lymphoma cell line decreased in the order benzoquinone (10.17) > hydroquinone (10.16)... 

Toxicology. Hydroquinone is moderately toxic and primarily affects the eyes. 

Ingestion of 5-12 g of hydroquinone has been reported to be fatal. In one nonfatal case of hydroquinone ingestion of approximately 1 g, tinnitus, dyspnea, cyanosis, and extreme sleepiness were observed. Although acute, high-dose oral ingestion produces noticeable central nervous system (CNS) effects in humans, no effects have been observed in workers exposed to lower concentrations in actual industrial situations. No signs of toxicity were found in subjects who ingested 3 00-500 mg hydroquinone daily for 3-5 months. ... 

Carlson AJ, Brewer NR Toxicity studies on hydroquinone. Proc Soc Exp Biol Med 84 684-688, 1953... 

Krasavage WJ, Blacker AM, English C et al Hydroquinone a developmental toxicity study in rats. Eundam Appl Toxicol 18 370-375, 1992... 

Murphy SJ, Schroeder RE, Blacker AM et al A study of developmental toxicity of hydroquinone in the rabbit. Eundam Appl Toxicol 19 214-221, 1992... 

Hodge HC, Sterner JH, Maynard EA, Thomas J Short-term toxicity tests on the mono and dimethyl ethers of hydroquinone.y Ind Hyg Toxicol 31 79-92, 1949... 

This study showed that hydroquinone was glycosated by the barley to form arbutln and was therefore effectively detoxified. If the equilibrium of the detoxification mechanism of a plant is sensitive to an oversupply of the toxic and detoxified compound, an oversupply of a detoxified compound could produce equilibrium amounts of the toxic compound. Cell culture bloassay (Table II) showed that hydroquinone is not significantly detoxified in vivo in leafy spurge, indicating the succeptiblllty of the plant to low levels of hydroquinone which could originate from an oversupply of arbutln. The observed toxicity of -benzoquinone in the cell cultures and seed bloassays also indicates that oxidation processes affecting hydroquinone will not detoxify the compound vivo. 

Tin radicals were generated by Noltes et al. in 1956, and their applications in organic chemistry were pioneered by Kuivila and co-workers. These species have proven to be of tremendous utility in organic chemistry, although their toxicity and other unfavorable properties have led to a search for substitutes. Interestingly, in the initial publication it was proposed that the reaction (equation 64) did not involve a free radical mechanism, as no inhibition by hydroquinone was detected. 

The mechanism of action of these compounds appears to involve inhibition of the enzyme tyrosinase, thus interfering with the biosynthesis of melanin. In addition, monobenzone may be toxic to melanocytes, resulting in permanent loss of these cells. Some percutaneous absorption of these compounds takes place, because monobenzone may cause hypopigmentation at sites distant from the area of application. Both hydroquinone and monobenzone may cause local irritation. Allergic sensitization to these compounds can occur. Prescription combinations of hydroquinone, fluocinolone... 

S H compounds. They may be generated during oxidation of ortho/para (but not meta) hydroquinones or aromatic diamines or hydroxytoluene compounds. The oxidation process may involve one-electron oxidation that could generate free radicals. There is increasing evidence that free radical metabolites represent possible toxic intermediates and/or ultimate carcinogens of chemicals (e.g., arylamines, haloalkanes). 

Thus, one-electron reduction catalyzed by cytochrome P-450 NADPH reductase tends to cause the toxicity of quinones via oxidative stress, whereas two-electron reduction produces the less toxic hydroquinones and so is a detoxication. 

Metabolism may involve many sequential steps, not just one phase 1 followed by one phase 2 reaction. Phase 1 reactions can sometimes follow phase 2 reactions, one molecule can undergo several phase 1 reactions, and cyclical or reversible metabolic schemes may operate. Thus, further metabolic transformations, sometimes termed phase 3 reactions, can convert a detoxified metabolite into a toxic product (see hexachlorobutadiene and hydroquinone). 

With chronic, higher level exposure, workers may suffer leukemia. Benzene is metabolized in the liver to a hydroquinone, which in the bone marrow is converted by the action of myeloperoxidase to the quinone and semiquinone products, which are reactive and therefore toxic. An unsaturated aldehyde, muconaldehyde is also a reactive metabolite, which could be involved in the toxicity (Fig. 6.29). 

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

Robertson, M.L., Eastmond, D.A. Smith, M.T. (1991) Two benzene metabolites, catechol and hydroquinone, produce a synergistic induction of micronuclei and toxicity in cultured human lymphocytes. Mutat. Res., 249, 201-209... 

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