Biomedical subjects
Publications and source records attributed to M Ehrich.
Chickens given 15 to 45 ppm dietary corticosterone 1 day prior to and 5 days following subcutaneous administration of 1 mg/kg 0,0-diisopropyl phosphorofluoridate (DFP) were not protected from either clinical delayed neuropathy, depression of neurotoxic esterase activity or advanced degenerative peripheral nerve myelinated fiber damage.
Fecal specimens from horses in Montgomery County, Md, and in Fairfax and Loudoun counties, Va, were examined for Clostridium perfringens type A enterotoxin and for C difficile cytotoxin (92 and 108 specimens, respectively). The toxins were found in feces from horses that had experienced an acute diarrhea syndrome and from clinically normal horses. The toxins did not appear to be primary determinants of the diarrhea syndrome, although they may have contributed to the spectrum of clinical entities observed.
Microsomes prepared from livers of chickens given enzyme inducers had increased capability to convert aflatoxin P1 to its glucuronide conjugate. This capability was 190% +/- 19 and 184% +/- 13 of control values (mean +/- S.E., N = 4) 96 h after intraperitoneal administration of 80 mg/kg beta-naphthoflavone or 3-methylcholanthrene, respectively. Glucuronidation of aflatoxin P1 was also increased 15 days after 500 mg/kg i.p. of a polychlorinated biphenyl mixture (to 471% +/- 111). Fifteen days on a low protein diet (containing 54% of normal levels) did not alter aflatoxin glucuronidation. Increased glucuronidation after administration of inducers was due to increased specific activity of the microsomal enzymes.
Detoxification of the organophosphate malathion in its activated form (malaoxon) was increased in livers of chickens given microsomal enzyme inducers (beta-naphthoflavone, 3-methylcholanthrene, butylated hydroxytoluene (BHT), or polychlorinated biphenyls). Positive correlations between inducer and microsomal enzyme activity were demonstrated for beta-naphthoflavone with demethylation of p-nitroanisole and for 3-methylcholanthrene and for BHT with cytochrome P450/448 and cytochrome b5. Malaoxon detoxification decreased in correlation with decreases in quantities of cytochrome P450/448 in birds fed a low-protein diet. Prediction of malaoxon detoxification was aided by using enzyme activities as dependent variables in the regression model, although only in birds given BHT were all of the 5 enzymes necessary for providing the best predictive model.
Chickens housed for 4.5 months in an environment of either low social stress or high social stress were administered triorthotolyl phosphate (TOTP) 180 mg/kg po. Clinical signs of delayed neuropathy were less in the low social stress group, unless moved to a high stress environment 24 hr before TOTP administration. Neurotoxic esterase activity was less than 20% of control values in all treatment groups. Birds from the low social stress group moved 24 hr prior to TOTP were more susceptible to inhibition of brain and liver cholinesterase activities following organophosphate administration. Liver microsomal enzyme activities (O-demethylase and aniline hydroxylase) were lowest in unmoved low social stress birds after TOTP, possibly protecting these birds from delayed neuropathy by reducing conversion of this organophosphate to its active metabolite.
Intraperitoneal administration of toxins of Clostridium difficile to mice resulted in loss of hepatic cytochrome P450 and peroxidation of microsomal lipids. Pretreatment with the microsomal enzyme inducer beta-naphthoflavone partially alleviated these effects and increased survival time of intoxicated animals.
1. Adult hens were given a mixture of polychlorinated biphenyls (0.5 and 2 g/kg Aroclor 1254), 3-methylcholanthrene (80 mg/kg) or beta-napthoflavone (80 mg/kg). 2. beta-Napthoflavone elevated activities of both microsomal and nonmicrosomal enzymes 48 hr after dosing, with cytochrome P-450 p-nitroanisole O-demethylase, aniline hydroxylase, and glutathione S-epoxytransferase at 319% +/- 25, 157% +/- 12, 410% +/- 26 and 120% +/- 3 of control values, respectively. 3. Aroclor 1254 and 3-methylcholanthrane also elevated microsomal enzyme activities, but did not increase the activity of glutathione S-epoxytransferase. 4. Drug metabolizing capability in control and experimental hens differed from that in rats and mice.
Toxins produced by Clostridium difficile are lethal to mice after i.p. administration. Among the alterations observed when mice were given a preparation containing both Toxin A and Toxin B were a 1.6 +/- 0.2 degrees C (mean +/- S.E., N = 7) depression of rectal body temperature, blood in the liver (318 +/- 13% of control levels) and a decrease in glutathione concentration (74 +/- 2% of control). Purified Toxin A and purified Toxin B were both able to alter these parameters. Toxin B, however, had a more profound effect on serum isocitrate dehydrogenase levels (raised to 198 +/- 18% of control) and liver O-demethylase activity (reduced to 64 +/- 8% of control), parameters sensitive to alteration in liver damage. The effects of Toxin B on these parameters were partially alleviated in mice pretreated with N-acetylcysteine (1.2 g/kg i.p.) and triamcinolone (120 mg/kg i.p.) and, although the percentage of survivors did not improve, survival time was increased from 3.0 +/- 0.1 hr to 4.6 +/- 0.5 and 5.7 +/- 1.3 hr, respectively, by these agents.
Human fecal extracts obtain substances mutagenic to Salmonella typhimurium TA 100. The mutagenicity of these extracts can be reduced enzymatically by inducible mammalian microsomal enzymes. Liver homogenates from rats administered the polychlorinated biphenyl mixture of Aroclor 1254 and corn oil were both effective, relative to the quantity of microsomal protein available in the enzyme preparation.
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We have produced antitoxin to the toxin of Clostridium difficile in rabbits and in goats. Antitoxin dilutions of 1/8,000 and 1/5,120 were capable of neutralizing lethal doses of the toxin in mice and in tissue culture, respectively.
The incidence of mutagens in the feces of 3 South-African populations at different risk levels for colon cancer has been determined. Lyophilized fecal samples were extracted with ether and the mutagenicity of the extracts determined using the Salmonella/mammalian microsome mutagenicity test. 19% of the samples from urban white South-Africans, a population at a high risk for colon cancer, were mutagenic using Salmonella typhimurium strain TA100. This incidence was significantly greater (p less than 0.001) than the incidence of mutagen excretion in the low-risk populations of urban blacks (2%) and rural blacks (0%). This pattern was also obtained using Salmonella typhimurium strain TA98. The incidence of mutagen excretion for urban whites was 10%, as compared to 5% and 2% for urban and rural blacks, respectively.
Trifluoromethyl derivatives of toluene, phenothiazine, benzimidazole and DDT were administered ip to male rats for 5 days and induction of hepatic microsomal enzymes catalyzing the metabolism of EPN, p-nitroanisole and aminopyrine measured. The addition of a trifluoromethyl substituent to toluene, phenothiazine and benzimidazole increased the inducing capacity of the parent molecule on p-nitroanisole metabolism. Dihalogenation of benzene with trifluoromethyl groups, regardless of position, resulted in induction of p-nitroanisole metabolism whereas halogenation of benzene with trichloromethyl groups did not. For these compounds, the size and electron-inducing capacity of the halogenated substituent may be relative to microsomal enzyme induction.
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Binding to tissue carboxylesterases has been suggested as an important mechanism of detoxification for several organophosphates. In this study DDVP, malaoxon, and paraoxon were inactivated, in vitro, by mouse liver under assay conditions that were consistent with a binding mechanism of inactivation. Binding of the three organophosphates was inhibited in livers of mice pretreated, 18 hr before sacrifice, with TOTP (triorthotolyl phosphate, 125 mg/kg, ip). Previous studies have shown that similar TOTP treatment enhanced the toxicity of malaoxon and paraoxon but did not alter the toxicity of DDVP. Both DDT (50 mg/kg, ip, given 4, 3.5, and 2.5 days before sacrifice) and dieldrin (16 mg/kg, po, given 4 days before sacrifice) increased liver/body weight ratios and decreased the duration of pentobarbital-induced loss of righting ability. Dieldrin increased liver carboxylesterase activity and liver binding of malaoxon and paraoxon but not of DDVP. In contrast, DDT did not increase liver carboxylesterase activity nor did it increase binding of malaoxon or paraoxon. Yet DDT pretreatment increased mouse liver binding of DDVP. Neither DDT nor dieldrin pretreatments altered the toxicity of subsequently administered DDVP. These results support the hypothesis that carboxylesterase binding does not represent an important mechanism for DDVP detoxification in the mouse. In other experiments, in vitro inactivation of malaoxon by binding was inhibited in livers of mice given DDVP (30 mg/kg, ip) 30 min before sacrifice. Similar DDVP pretreatment potentiated the anticholinesterase action of malaoxon (10 mg/kg, ip). Thus, even though DDVP toxicity was not altered by DDT- or dieldrin-induced changes in organophosphate binding, DDVP inhibited malaoxon binding and increased malaoxon toxicity.
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