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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Industrial Chemicals. Lyon (FR): International Agency for Research on Cancer; 2018. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 115.)
4.1. Absorption, distribution, metabolism, excretion
4.1.1. Absorption, distribution, excretion
(a) Humans
Organ toxicity after accidental or intentional exposure to hydrazine demonstrated absorption into the systemic circulation and distribution to target tissues (Nagappan & Riddell, 2000; Kao et al., 2007). After occupational exposure, hydrazine was absorbed and excreted in the urine (Nomiyama et al., 1998a). Exposure to the therapeutic drug isoniazid, containing a hydrazine group, resulted in excretion of hydrazine and its metabolites in the urine (Timbrell et al., 1977; Blair et al., 1985; Donald et al., 1994; Preziosi, 2007).
(b) Experimental systems
Absorption of hydrazine was rapid after either oral or dermal administration in experimental animals. Hydrazine was detected in femoral blood within 30 seconds after application of a dose of 3–15 mmol/kg bw to an area of shaved chest skin of anaesthetized dogs. The serum concentration of hydrazine peaked within the first hour for most doses, followed by a slow decline over a 6-hour holding period. Unchanged hydrazine was excreted in the urine. Mortality was high across the dosing range (Smith & Clark, 1972). When hydrazine hydrate (corresponding to hydrazine free base at 3–81 mg/kg bw) was given orally (gavage) to rats, hydrazine was at its greatest concentration in the plasma and liver within 30 minutes after dosing, with the exception of a peak in plasma concentration 90 minutes after administration of the highest dose (Preece et al., 1992a). The liver to plasma ratio of hydrazine decreased with increasing dose, suggesting saturation of uptake by the liver. An effect on dose elimination was also observed, with about 40% of the lowest dose but less than 20% of the highest dose being excreted in the urine within 24 hours after administration. Dambrauskas & Cornish (1964) investigated the fate of hydrazine in rats given hydrazine hydrate at a dose of 60 mg/kg bw by subcutaneous injection. The dose was well distributed, with hydrazine detected in adipose, blood, brain, kidney, liver, lung, muscle, skin, and other tissues within 2 hours after dosing. About 13% of the total administered dose was recovered in the assayed tissues as unchanged hydrazine, with the highest concentration present in the kidney (41–56 µg/g). Hydrazine (8% of the total administered dose) was excreted in the urine. Matsuyama et al. (1983) provided additional evidence that hydrazine crosses the blood–brain barrier in rats. After intravenous injection, hydrazine was detected in the brain accompanied by an increase in gamma-aminobutyric acid (GABA) over a period of 10 hours. Hydrazine was rapidly absorbed and distributed to tissues when administered as hydrazine sulfate at a dose of 0.31 mmol/kg bw by subcutaneous injection in rats (Kaneo et al., 1984). Springer et al. (1981) recovered up to 75% of [15N]-labelled hydrazine from single doses of 1 mmol/kg bw administered by various injection routes (intraperitoneal, subcutaneous, intravenous) in rats. Up to 25% of the total administered dose was recovered as nitrogen (N2) in expired air within 48 hours. An additional 50% was excreted in the urine as unchanged hydrazine and acid-labile metabolite(s). The disappearance of intravenously administered hydrazine from blood was described as biphasic, with calculated half-lives of 0.74 and 27 hours. In mice, intraperitoneal administration of [15N]-labelled hydrazine sulfate at 1 mmol/kg bw resulted in rapid distribution to tissues including blood, brain, liver, kidney, and lung (Nelson & Gordon, 1981). Clearance from tissues was extensive by 24 hours. About 30% of the administered dose was recovered as N2 and 40% was recovered in the urine as hydrazine and metabolites within 48 hours after injection (Nelson & Gordon, 1981).
Mice excreted about 50% of an administered dose of either 40 or 60 mg/kg bw as unchanged hydrazine in the urine within 48 hours after a subcutaneous injection. Less than 1.5% of the administered hydrazine remained in each carcass at this time-point. The unrecovered dose was assumed to be metabolites (Dambrauskas & Cornish, 1964).
4.1.2. Metabolism
(a) Humans
Hydrazine was metabolized to acetylhydrazine (monoacetylhydrazine) in exposed workers (Nomiyama et al., 1998a). In male Japanese workers, the rate of acetylation was dependent on polymorphisms in N-acetyltransferase (NAT2), with half-lives of about 2 and 4 hours in rapid and slow acetylators, respectively (Koizumi et al., 1998). Acetylhydrazine and diacetylhydrazine have been detected in the urine of subjects receiving isoniazid (Ellard & Gammon, 1976; Timbrell et al., 1977). Oxidative metabolism of hydrazine was demonstrated in human microsomes based on disappearance of the chemical over time from the incubation mixture; however, the rate of metabolism was slower than in rat microsomes (Jenner & Timbrell, 1995). A review of isoniazid metabolism indicated that pathways of hydrazine biotransformation are similar in humans and other mammals (Preziosi, 2007). The metabolism of hydrazine is discussed in greater detail below.
(b) Experimental systems
Pathways of hydrazine metabolism in experimental animals include oxidation and acetylation (Colvin, 1969; Fig. 4.1). Acetylhydrazine and/or diacetylhydrazine have been observed in the urine of animals treated with hydrazine. The presence and/or relative abundance of these acetylated metabolites are species-dependent. Bollard et al. (2005) detected diacetylhydrazine in the urine of rats and mice treated orally with hydrazine hydrochloride at a dose of 100 or 250 mg/kg bw. In contrast, acetylhydrazine was detected in the urine in rats, but not in mice. This result was attributed to higher activity of N-acetyl transferase in the mouse. Dogs, unlike rats and mice, have little to no capacity to acetylate hydrazine (McKennis et al., 1959). This limitation may have contributed to the prolonged elimination of hydrazine in dogs as reported by Smith & Clark (1972). Rabbits treated with hydrazine excreted diacetylhydrazine in the urine (McKennis et al., 1959). Kaneo et al. (1984) demonstrated that metabolism of hydrazine to acetylhydrazine in rats was reversible. Acetylhydrazine may give rise to a carbon-centred acetyl radical or carbocation, capable of binding to macromolecules or oxidation to carbon dioxide (CO2) (Sinha, 1987; Mörike et al., 1996; Preziosi, 2007). Hydrazine may also give rise to hydrazones (Preziosi, 2007). The metabolite 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid, a derivative of oxoglutarate hydrazone, was found in the urine of rats and mice treated with hydrazine (Nelson & Gordon, 1981; Delaney & Timbrell, 1995; Bollard et al., 2005). Hydrazine is oxidized to N2 in rats and mice (Nelson & Gordon, 1981; Springer et al., 1981). Degradation of hydrazine to ammonia (NH3) may be possible, especially in dogs (McKennis et al., 1959; Colvin, 1969; Preziosi, 2007). Oxidative metabolism of hydrazine was catalysed primarily by cytochrome P450s (CYPs) in rat microsomes (Noda et al., 1987; Jenner & Timbrell, 1995). Mixed function oxidases may also play a role (Jenner & Timbrell, 1995). Results from incubation in rat hepatocytes suggested the involvement of CYP2E1, CYP2B1, and CYP1A1/2 in the metabolism of hydrazine (Delaney & Timbrell, 1995). CYP activity was demonstrated in the metabolism of [15N2]-[14C]-labelled acetylhydrazine to N2 and CO2 in the rat (Mörike et al., 1996). A hydrazine radical, potentially giving rise to a diimide (diazene), was identified in microsomal incubations of hydrazine using a spin-trapping method (Noda et al., 1985).
Fig. 4.1
Proposed metabolic scheme for hydrazine in mammals
4.2. Mechanisms of carcinogenesis
The evidence on the “key characteristics” of carcinogens (Smith et al., 2016) – concerning whether hydrazine is genotoxic, induces oxidative stress, alters cell proliferation, cell death or nutrient supply, and modulates receptor-mediated mechanisms – is summarized below.
4.2.1. Genetic and related effects
Table 4.1
Genetic and related effects of hydrazine in human and rodent cells in vitro.
Table 4.2
Genetic and related effects of hydrazine in experimental animals in vivo.
(a) Humans
No data on exposed humans were available to the Working Group.
One study reported the induction of single-strand breaks and alkali-labile sites (comet assay) in human lung cells in vitro (Robbiano et al., 2006).
(b) Experimental systems
Considerable information was previously reviewed by the IARC Monographs Working Group regarding whether hydrazine is genotoxic in experimental systems (IARC, 1999). Multiple studies identified N7-methylguanine and O6-methylguanine in the livers of mice, rats (including neonates) and hamsters treated with hydrazine in vivo. The available data suggested that the DNA methylation mechanism involved reaction of hydrazine with endogenous formaldehyde, followed by metabolism of the resulting hydrazone to a methylating agent, most likely diazomethane. Other reports concerned the formation of DNA adducts (not characterized) in M13mp18 viral DNA in vitro.
One study found that hydrazine induced organ-specific genotoxicity in mice, and that the target organs for DNA damage (alkaline comet assay) depended on the route of administration. DNA damage was found in the stomach, liver, and lungs of mice given hydrazine as a single intraperitoneal dose at 100 mg/kg bw. When the same dose was administered orally, DNA damage was also found in the colon and brain (Sasaki et al., 1998). More recently, another study reported the induction of single-strand breaks and alkali-labile sites (comet assay) in primary lung cells from male rats as well as in the lungs of rats given a single oral dose of hydrazine (Robbiano et al., 2006). Lack of induction of sister-chromatid exchanges in bone marrow or liver of mice, and conflicting results on induction of micronuclei in mouse bone-marrow cells (in one study out of three), were observed (IARC, 1999).
Hydrazine induced DNA strand breaks in rat hepatocytes and unscheduled DNA synthesis in mouse hepatocytes. There were conflicting results for the induction of gene mutations in mouse lymphoma L5178Y cells (one positive result and two negative, all in the absence of exogenous metabolic activation). Hydrazine induced sister-chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, but gave negative results for the induction of chromosomal aberrations in rat liver RL1 cells (IARC, 1999).
Hydrazine was mutagenic in yeast and bacteria, induced DNA damage in bacteria, and caused somatic mutations in Drosophila (IARC, 1999).
4.2.2. Oxidative stress
(a) Humans
No data in exposed humans were available to the Working Group.
In human hepatoma HepG2 cells, hydrazine (0.25–2.0 mM) depleted reduced glutathione in a concentration-dependent manner, whereas reactive oxygen species (ROS) were decreased, as assessed using the dye 2′,7′-dichlorodihydrofluorescein diacetate (Olthof et al., 2009).
(b) Experimental systems
(i) Non-human mammals in vivo
In Wistar rats fed diets containing 0.5% hydrazine dichloride for 7 days, there were significant increases in lipid-soluble fluorophores (lipofuscin) in the liver, heart, muscle, and spleen (Antosiewicz et al., 2002). This index of oxidative stress induction by hydrazine was diminished in the heart and skeletal muscle by the antioxidant α-tocopherol diacetate.
In Wistar rats, hydrazine (intraperitoneal dose of 80 mg/kg bw) decreased hepatic glutathione levels, increased levels of malondialdehyde (a measure of lipid peroxidation), and increased levels of 8-hydroxy-2′-deoxyguanosine DNA adducts (8-OHdG, a measure of oxidative DNA damage). These changes were prevented by tea melanin (Hung et al., 2003).
In Sprague-Dawley rats, hydrazine dihydrochloride (0, 120, or 240 mg/kg bw by gavage) increased levels of the precursor amino acids of glutathione biosynthesis in the urine and/or plasma and increased plasma 5-oxoproline (a product of glutathione metabolism) (Bando et al., 2011).
Several studies have reported suppression by antioxidants of the induction of megamitochondria (enlarged and abnormally shaped mitochondria that are thought to arise by membrane fusion) by hydrazine. For instance, in Wistar rat liver, hydrazine-induced formation of megamitochondria, and accompanying increases in lipid peroxidation were suppressed by co-treatment with coenzyme Q10 (CoQ10). CoQ10 did not prevent the decrease in reduced glutathione that was observed in rats treated with hydrazine (Adachi et al., 1995). The formation of megamitochondria in the liver of Wistar rats fed diets containing 1.0% hydrazine for 7 days was also suppressed by α-tocopherol (intraperitoneal dose of 700 mg/kg bw). A marked increase in hepatic level of lipid-soluble fluorophores, an indicator of oxidative stress, was also observed in hydrazine-treated rats; however, these increases were not prevented by α-tocopherol (Antosiewicz et al., 1994). The formation of megamitochondria in the livers of Wistar rats fed diets containing 0.5% hydrazine for 7 days was suppressed by various free radical scavengers including CoQ10, α-tocopherol, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-OH-TEMPO), and by allopurinol, a xanthine oxidase inhibitor (Wakabayashi et al., 1997). In addition, 4-OH-TEMPO lowered hepatic lipid peroxidation, assessed by measuring levels of thiobarbituric acid reactive substances (TBARS) and of lipid-soluble fluorophores. Allopurinol was less effective than 4-OH-TEMPO in preventing loss of mitochondrial phosphorylating ability and in preventing lipid peroxidation in liver (Matsuhashi et al., 1997; Wakabayashi et al., 1997). An increase in the rate of generation of hydrogen peroxide was also observed in isolated liver mitochondria obtained from Wistar rats that had been fed diets containing 1% hydrazine for 3 days (Karbowski et al., 1999). [The Working Group noted that induction of megamitochondria by hydrazine is probably due to free radicals generated by exposure to this agent, and that the hepatotoxicity of hydrazine is probably due to induction of oxidative stress.]
Perfusion of Sprague-Dawley rat livers with hydrazine, acetylhydrazine, or isoniazid at 5 mM in the presence of the spin-trapping agent α-phenyl-tert-butylnitrone produced the carbon-centred radical that was shown to be the same acetyl radical (Sinha, 1987).
(ii) Non-human mammalian cells in vitro
During CYP-mediated oxidative metabolism of hydrazine by rat liver microsomes, the formation of a free radical intermediate was detected by electron spin resonance spectroscopy using α-phenyl-tert-butylnitrone as the spin-trapping agent; the radical species trapped with α-phenyl-tert-butylnitrone was identified as a hydrazine-derived metabolite by mass spectrometry (Noda et al., 1985). Inhibitors of CYP, and the antioxidant ascorbic acid decreased the generation of hydrazine radical by rat liver microsomes (Matsuki et al., 1991).
Lipid peroxidation (TBARS) was increased significantly in rat liver slices incubated with hydrazine at 15 mM for 10 hours. This increase was associated with extensive hepatic necrosis (Walubo et al., 1998).
Exposure of primary rat hepatocytes (isolated from Fischer 344 rats) to hydrazine (at 25 mM and above) reduced catalase activity, depleted reduced glutathione, and increased oxidized glutathione and lipid peroxidation (TBARS), while ROS was increased at hydrazine concentrations of 100 mM and above (Hussain & Frazier, 2002).
Hydrazine (8 mM) increased the formation of hydrogen peroxide and ROS, and protein carbonylation in hepatocytes isolated from Sprague-Dawley rats. ROS formation and protein carbonylation were decreased by a ROS scavenger (4-OH-TEMPO) and by a CYP inhibitor (1-aminobenzotriazole) (Tafazoli et al., 2008).
Hung et al. (2003) showed that melanin derived from tea reduced hydrazine-induced free radical formation in rat hepatocytes isolated from Wistar rats, as assessed by measuring chemiluminescence intensity.
In hepatocytes isolated from Sprague-Dawley rats, the effects of hydrazine and isoniazid on lipid peroxidation and mitochondrial depolarization were significantly reduced by pre-treatment with N-acetylcysteine. Hydrazine (8 mM) significantly increased ROS whether or not glutathione was depleted, and also increased lipid peroxidation and mitochondrial membrane depolarization (Heidari et al., 2013).
Incubation of primary Wistar rat hepatocytes with hydrazine (2 mM) induced the formation of megamitochondria, decreased the mitochondrial membrane potential, and increased intracellular levels of ROS (assessed using 2′,7′-dichlorodihydrofluorescein diacetate) (Teranishi et al., 1999). These changes were suppressed by co-treatment of hepatocytes with the free radical scavenger CoQ10 (1 μM).
In primary cultures of Wistar rat hepatocytes, mitochondria were enlarged by hydrazine, and mitochondria were substantially larger in hepatocytes isolated from rats pre-treated with phenobarbital and then incubated with hydrazine. The effect of phenobarbital was attributed to the induction of CYP, which had been reported to metabolize hydrazine and generate free radicals (Noda et al., 1987). In addition, compared with controls, levels of malondialdehyde in homogenates of hepatocyte cultures treated with hydrazine at 2 mM were elevated (155%) after incubation for 4 hours and significantly increased (240%) after incubation for 22 hours (Karbowski et al., 1997).
(iii) Acellular systems
Hydrazine (0.5 mM) produced fragmentation of calf thymus DNA in a cell-free system containing manganese (Mn) or copper (Cu) ions. DNA damage induced by hydrazine plus Mn(II) or Mn(III) was inhibited by hydroxyl radical scavengers or superoxide dismutase, but not by catalase; while DNA damage caused by hydrazine plus Cu(II) was inhibited by catalase, but not by hydroxyl radical scavengers or superoxide dismutase. Electron spin trapping using 5,5-dimethyl-1-pyrroline N-oxide confirmed that hydrazine plus Mn(III) produced hydroxyl free radical via superoxide and not via hydrogen peroxide. Thus, ROS may also be produced by nonenzymatic activation of hydrazine (Yamamoto & Kawanishi, 1991).
4.2.3. Altered cell proliferation, death, or nutrient supply
(a) Humans
No data were available to the Working Group.
(b) Experimental systems
(i) In vivo
In Syrian golden hamsters given drinking-water containing hydrazine sulfate (170, 340, or 510 mg/L for up to 21 months), increases in megalocytosis, intranuclear inclusions, bile duct hyperplasia, and foci of cellular alteration were observed after 18 months in the groups receiving the intermediate and highest doses. However, incorporation into liver DNA of 14C-thymidine, administered before termination as an index of cell replication, was not different in any of the exposure groups compared with controls at any interim evaluation (FitzGerald & Shank, 1996).
No studies were identified that showed suppression of apoptosis by hydrazine. In an inhalation study, increases in the incidence of apoptosis based on histological criteria were reported in the nose of Fischer 344 rats exposed to hydrazine (750 ppm) for 1 or 10 hours. Increased incidences of proliferative nasal lesions, including epithelial hyperplasia and adenoma, were also observed in these rats held for up to 28 months after exposure (Latendresse et al., 1995).
Hepatic steatosis and hyperlipidaemia were induced in Wistar rats given hydrazine as a single intraperitoneal injection at 50 mg/kg bw. Compared with controls, exposed rats had increased levels of triglycerides, cholesterol, free fatty acids, and total lipids in plasma and liver tissue. Hydrazine also caused a decrease in levels of triglycerides and total lipids in adipose tissue (Vivekanandan et al., 2007). [The Working Group noted that increased mobilization of triglycerides from adipose tissue to the liver by hydrazine may contribute to the development of hepatic steatosis by this chemical.]
In C57Bl/6 mice, significant increases (more than twofold) in the hepatic expression of several genes involved in triglyceride and cholesterol synthesis, lipid transport, and fatty acid oxidation were detected 24 hours after administration of a single oral dose of hydrazine sulfate (100 mg/kg bw). The gene expression profiles resulting from hydrazine exposure were consistent with production and intracellular transport of hepatic lipids being favoured over removal of fatty acids (Richards et al., 2004).
(ii) In vitro
In hepatocytes isolated from Wistar rats, pre-labelled with [14C]palmitate, and incubated with 2–12 mM hydrazine, the percentage of radiolabelled triglycerides appearing in the medium decreased with increasing concentrations of hydrazine [these results indicated that reduced secretion of triglycerides from liver cells might also be a factor in hydrazine-induced hepatic steatosis] (Waterfield et al., 1997). Waterfield et al. (1997) also reported the following hepatic or hepatocellular effects: lactate dehydrogenase leakage, adenosine triphosphate (ATP) and glutathione S-transferase depletion, increase in citrulline level, inhibition of protein synthesis, taurine leakage, and triglyceride accumulation.
Dilworth et al. (2000), using metabolically competent rat liver spheroids, also showed ATP depletion after hydrazine treatment that required even higher concentrations than hepatocytes in primary culture. Garrod et al. (2005) observed an increase in triglycerides and β-alanine, combined with a decrease in hepatic glycogen, glucose, choline, taurine, and trimethylamine-N-oxide (TMAO) in the rat liver 24 hours after a dose of hydrazine of 90 mg/kg bw. In the renal cortex, 2-aminoadipate, and β–alanine increased, which concurred with a decrease in TMAO, myo-inositol, choline, taurine, glutamate, and lysine.
4.2.4. Receptor-mediated effects
(a) Humans
No data were available to the Working Group.
(b) Experimental systems
In C57Bl/6 mice, a single dose of hydrazine sulfate at 100 or 300 mg/kg bw increased hepatic gene expression by peroxisome proliferation-activated receptor (PPAR) and sterol regulatory element-binding protein transcription factors after 24 hours (Richards et al., 2004)
To detect possible toxicity pathways with hydrazine in Sprague-Dawley rat liver, a combination of genomics, proteomics, and metabolomics was used to detect changes in mRNA, proteins, and endogenous metabolites after a single oral dose (30 or 90 mg/kg bw). The results of these combined techniques suggested that hydrazine can affect hepatic oxidative stress, Ca2+ concentration, and thyroid hormone homeostasis, glucose and lipid metabolism; several mechanistic pathways for toxicity in the rat liver were described (Klenø et al., 2004a, b).
In addition to hepatotoxicity, effects on the central nervous system in rodents have been associated with changes in GABA levels. Specifically, these changes were caused by depletion of pyridoxal phosphate, which requires gamma-aminobutyrate aminotransferase and glutamate decarboxylase (IPCS, 1987a).
4.2.5. Other mechanisms
No additional mechanistic data in exposed humans or human cells were available to the Working Group.
Concerning epigenetic effects, hydrazine increased the labelling of methylguanines upon co-administration of L-[methyl-14C]methionine or [14C]formate in rodents (Lambert & Shank, 1988). In Syrian golden hamsters given drinking-water containing hydrazine sulfate (170–510 mg/L) for up to 21 months, hypomethylation of cytosines occurred at the highest exposure level (FitzGerald & Shank, 1996). In this 21-month study, Zheng & Shank (1996) reported hypomethylation in the p53 tumour suppressor gene and in the c-jun proto-oncogene, and hypermethylation in the c-Ha-ras proto-oncogene and in the DNA methyltransferase gene. No changes were detected for c-fos, c-myc, and γ-glutamyltranspeptidase. Lambert & Shank (1988) proposed a pathway for the generation of a methylating elctrophile from formaldehyde hydrazine, a condensation product of hydrazine and formaldehyde (Fig. 4.2).
Fig. 4.2
Proposed pathway for the metabolic generation of a methylating electrophile from formaldehyde hydrazone, a condensation product of hydrazine and formaldehyde
Inflammatory infiltrates were only of minimal severity in animals killed after a single exposure or 10 one-hour exposures to hydrazine at 750 ppm, or at least 2 years after exposure (Latendresse et al., 1995).
4.3. Data relevant to comparisons across agents and end-points
For all compounds evaluated in the present volume of the IARC Monographs, including hydrazine, analyses of high-throughput screening data generated by the Tox21 and ToxCastTM research programmes of the government of the USA (Kavlock et al., 2012; Tice et al., 2013) are presented in the Monograph on 1-bromopropane, in the present volume.
4.4. Cancer susceptibility
No data were available to Working Group.
4.5. Other adverse effects
4.5.1. Humans
Hydrazine is hepatotoxic, nephrotoxic, immunotoxic, and neurotoxic in humans. Hydrazine produces strong irritation of the skin, eye, and mucous membranes, and can also cause skin sensitization. After ingestion, reported systemic effects are vomiting, muscle tremor, convulsions, seizures, paresthesia, anorexia, weight loss, kidney damage, and centrolobular fatty changes of the liver (SCOEL, 2010). No data concerning reproductive toxicity in humans were available to the Working Group (HSDB, 2010).
4.5.2. Experimental systems
The toxicological effects of hydrazine in experimental animals were comparable to those seen in humans, with pronounced effects on the liver, kidneys and lungs. In the rat, liver accumulation of lipids, swelling of mitochondria, and formation of microbodies in the hepatocytes were observed. In general, similar hepatic lesions were observed in rat, mice, hamsters, dogs, and monkeys, but the intensity of the effects was species-dependent. In addition, effects in experimental animals have also been observed on the proximal tubular kidney cells, lungs, central nervous system, haematological system, and ocular regions, while behavioural effects like lethargy and depression were also reported (HSDB, 2010).
Hydrazine and mono-acetyl hydrazine are formed as reactive metabolites of isoniazid, and may play a role in its toxicity (reviewed by Hassan et al., 2015). In the metabolism of isoniazid, NAT2 is responsible for the formation of acetyl hydrazine, which is further oxidized by CYP2E1 to N-hydroxy acetyl hydrazine that is eventually converted to acetyl diazine. The latter compound may be the toxic metabolite itself, or break down further to the reactive acetyl onium ion, acetyl radical, and ketene, which in turn can bind covalently to hepatic macromolecules, resulting in liver toxicity.
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