Methylation in rats

Pawlowska D, Moniuszko-Jakoniuk J, Soltys M. 1985b. The effect of chronic physical exercise on the activity of hydrolytic enzymes in acute poisoning with parathion-methyl in rats. Pol J Pharmacol Pharm 37 639-646. 

Brealey, C.J. (1980). Comparative Metabolism of Pirimiphos-methyl in Rat and Japanese Quail. Ph.D. Thesis, University of Reading, UK. 

Jensen et al. [87] provided evidence that the in vitro methylation of DNA was carried out by microsomally-activated DMNA and that the methylation was correlated with formaldehyde production. Sagelsdorff et al. [88] showed DNA methylation in rat liver by daminozide, 1, 1-dimethylhydrazine, and DMNA. Studies with other nitroso compounds also confirmed the formation of hydros derivatives, aldehydes, and nitrite by rat liver microsomes and by purified cytochrome P-450 IlBl [84]. The sequence of specific methylation of DNA by N-nitix>so compounds shares a common intermediate, methyl diazonium ion [89]. 

Within the hver, SULT activity is predominant, but further methylation may also occur. Catechin glucuronides were subsequently sulfated, as well as methylated, in rat hver after in situ perfusion [49]. Piskula and Terao [73] also reported that SULT activity for epicatechin was present exclusively in liver. Within hepatocytes, it is also possible that catechin glucmonides are deglucu-ronidated and then reglucuronidated before reaching systemic circulation [49]. 

Pascale, R.M., Simile, M.M., Satta, G., Seddaiu, M.A., Daino, L., Pinna, G., Vmci, M.A., Gaspa, L., and Feo, F. (1991). Comparative effects of L-methionine, S-adenosyl-L-methionine and 5 -methylthioadenosine on the growth of preneoplastic lesions and DNA methylation in rat liver during the early stages of hepatocarcinogenesis. Anticancer Res. 11,1617-1624. 

In 1959 Clinton and coworkers reported the first synthesis of some pyrazole fused androstane derivatives and described their biological activity (B-76MI40404). Stanazolol (695) or 17-methyl-2iT-5o -androst-2-eno[3,2-c]pyrazol-17/3-ol was 10 times as active as 17a -methyltestosterone in improving nitrogen retention in rats (B-80MI40406), and its myotrophic activity was only twice that of 17a-methyltestosterone. It is used as an anabolic steroid with no lasting adverse side effects. 

The metabolic fate of l-(4-methoxy-6-methyl-2-pyrimidinyl)-3-methyl-5-methoxy-pyrazole, mepirizole, has been investigated in rats, rabbits and man. Three metabolites, (751), (752) and (753), were identified in human urine (76CPB804). 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Propylthiouracil (PTU), but not methyl-mercaptoi-midazole (MMI), has an additional peripheral effect. It inhibits the monodeiodination of thyroxine to triiodothyronine by blocking the enzyme 5 mono-deiodinase [1]. In humans the potency of MMI is at least 10 times higher than that of PTU, whereas in rats PTU is more potent than MMI. The higher potency of MMI in humans is probably due to differences in uptake into the thyroid gland and subsequent metabolism, because in vitro inhibition of thyroid peroxidase by MMI is not significantly more potent than by PTU [1, 6]. Whether antithyroid drags have additional immunosuppressive actions is a matter of discussion [1, 2]. 

Hematological Effects. No information was found regarding hematological effects in humans following exposure to methyl parathion. Repeated oral exposure to methyl parathion resulted in decreased mean corpuseular volume in one study and decreased hematocrit and erythrocyte count in another study in rats. Chronic ingestion of methyl parathion induced reduction of mean hemoglobin, hematocrit, and erythrocyte eounts in rats. 

The LC50 values of methyl parathion have been established in rats. A 1-hour LC50 of 200 mg/m and a 4-hour LC50 of 120 mg/m for males were determined by Kimmerle and Lorke (1968). One-hour LC50 values of 257 mg/m for male rats and 287 mg/m for female rats were determined for 70-80% pure methyl parathion by EPA (1978e) the rats were exposed to aerosols of respirable size. Survivors of toxic doses recovered clinically by 10-14 days postexposure. Sex-related differences in acute mortality of rodents have also been observed after exposure to methyl parathion by other routes (Murphy and Dubois 1958). 

Thymic hemorrhage and congested cerebral blood vessels occurred in rats exposed to a 1-hour LC50 of methyl parathion described in Section 3.2.1.1 (EPA 1978e). These are probably nonspecific agonal lesions. 

The LD50 values for methyl parathion were compared to those for methyl paraoxon, the active metabolite of methyl parathion, in rats, guinea pigs, and mice by Miyamoto et al. (1963b). Methyl paraoxon was 5.4 times more potent than methyl parathion in male rats, 5 times more potent in male guinea pigs, and 1.6 times more potent in mice. 

A significant increase in heart-to-body-weight ratio occurred in female rats exposed to 2.5 mg/kg/day methyl parathion in the diet for 2 years, but not in rats exposed to either 0.025 or 0.25 mg/kg/day methyl... 

Male and female rats exposed to 2.5 mg/kg/day methyl parathion in the diet for 2 years had statistically significant reduced body weights when compared to vehicle controls (Suba 1984). This effect was not consistent throughout the study and did not occur in rats exposed to either 0.025 or 0.25 mg/kg/day methyl parathion. Mean food consumption values were significantly elevated in male rats but only within the first 13 weeks of the 2-year exposure to 2.5 mg/kg/day methyl parathion (Suba 1984). Females exposed to 2.5 mg/kg/day methyl parathion had significantly reduced food intake values during the first 2 weeks of exposure, but intake was significantly elevated from week 3 to termination. Effects on food... 

No dose-response relationship can be established for the developmental toxicity of methyl parathion from the available database. All reliable LOAEL values in rats for developmental effects for the acute- and intermediate-duration categories are recorded in Table 3-3 and plotted in Figure 3-2. 

The available evidence suggests that excretion of methyl parathion metabolites in humans and animals following acute oral exposure is essentially the same and occurs rapidly. Excretion occurs primarily via the urine. Methyl parathion can also be excreted in breast milk, although it has been detected only in a limited number of samples from women of central Asia, for which exposure data were not available (Lederman 1996) (see also Section 3.4.2.2). A study in rats also reported excretion of methyl parathion in the milk (Golubchikov 1991 Goncharuk et al. 1990). 

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