Hepatocyte hypertrophy

Rats exposed to 2 000 ppm 6 hours/day, 5 days/week, for 2 weeks exhibited lethargy and decreased response to noise. When exposed over a period of 90 days to 1000 ppm, there was nose and eye irritation, gel-like casts in seminal fluid of males, and increases in liver and kidney weight. Microscopic examination revealed hepatocyte hypertrophy and renal hyalin droplet formation in males. The toxicity of MIAK after inhalation exposure was not as extensive or severe as that resulting from a prior study in which male rats were dosed orally with 2000mg/kg/day for 13 weeks. 

More recently, however, in cynomologous monkeys, a nonhuman primate, some limited responses to these compounds have been seen with a twofold increase in liver weight, hepatocyte hypertrophy, an increase in peroxisomes (2.7x), and an increase in mitochondria. However, no DNA damage was detected. With humans taking ciprofibrate, only limited peroxisome proliferation was seen, and there was no increase in acyl CoA oxidase. Thus, the question is, "are humans at risk " In order to understand this, the mechanism needs to be understood. 

In the rodent, frequently a dose-related increase of the liver weight paralleled by hepatocytic hypertrophy occurs. This phenomenon is often due to induction of hepatic drug metabolizing enzymes. It is obviously over-expressed in the rodent species with the aim to faster metabolise xenobiotics and also degradation... 

In the liver, hepatocyte hypertrophy and centrilobular necrosis are seen. There is also an increase in liver cancers. Immune modulation has been described in both chickens and mice showing decreased antibody titers. Nervous system effects include tremors, loss of equilibrium, and changes in cellular chemistry in monkeys. 

Treatment with each of the three conazoles resulted in similar histopathologi-cal and clinical chemistry results. A common nongenotoxic mechanism of rodent hepatocarcinogenesis involves the activation of the constitutive androstane receptor (CAR) (see Chapter 16), hepatocyte hypertrophy, the induction of CYP2B, the induction of cell proliferation, and the inhibition of apoptosis has been proposed for conazoles (Chen et al. 2009 Peffer et al. 2007). These alterations were produced by... 

Marked increases in liver weight and hepatocyte hypertrophy have been shown to be a reflection of peroxisome proliferation [30-33]. Hepatocyte hypertrophy and increased liver weight induced by peroxisome proliferation are known to be specific in rodents [34], and humans are not susceptible to peroxisome proliferation [30,31]. Therefore, the effects on the liver are considered unlikely to be relevant to human health. 

Chronic inhalation exposure to 0, 75, 250 or 750 ppm [0, 0.32, 1.1 or 3.3 g/m ] ethylbenzene for 6 h per day on five days per week for 104 weeks caused an increased incidence of renal tubule h erplasia in male Fischer 344/N rats and increased severity of spontaneous, age-related chronic progressive nephropathy in males and females. Male B6C3Fi mice developed an increased incidence of alveolar epithelial metaplasia, syncytial alterations of hepatocytes, hepatocellular hypertrophy, hepatocyte necrosis and thyroid gland follicular-cell h erplasia. Exposure to ethylbenzene also caused an... 

Peroxisome proliferation is consistently associated with hepatomegaly, which arises from a combination of cellular hypertrophy and hyperplasia. Studies on fine structure of hepatocytes revealed that the increase in hepatocyte size was associated with the predominant increase in peroxisomes and modest increase in smooth endoplasmic reticulum (SER). Rats exposed to peroxisome proliferators exhibit 7- to 10-fold increases in peroxisomal relative volume and surface area as evidenced by morphometric analysis of liver sections. The increase in peroxisomal relative volume is due to the increases in both volume and number of peroxisomes. In contrast, the increase in SER surface area and volume rarely exceeds twofold. The magnitude of increase in cellular DNA and... 

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