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1. |
Small Intestinal Cytochromes P450 |
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Critical Reviews in Toxicology,
Volume 21,
Issue 6,
1992,
Page 407-422
KaminskyLaurence S.,
FascoMichael J.,
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摘要:
AbstractSmall intestinal cytochromes P450 (P450) provide the principal, initial source of biotransformation of ingested xenobiotics. The consequences of such biotransformation are detoxification by facilitating excretion, or toxification by bioactivation. P450s occur at highest concentrations in the duodenum, near the pylorus, and at decreasing concentrations distally—being lowest in the ileum. Highest concentrations occur from midvillus to villous tip, with little or none occurring in the crypts of Lieberkuehn. Microsomal P4503A, 2C8-10, and 2D6 forms have been identified in human small intestine, and P450s 2B1, possibly 2B2, 2A1, and 3A1/2 were located in endoplasmic reticulum of rodent small intestine, while P4502B4 has been purified to electrophoretic homogeneity from rabbit intestine. Some evidence indicates a differential distribution of P450 forms along the length of the small intestine and even along the villus. Rat intestinal P450s are inducible by xenobiotics—with phenobarbital (PB) inducing P4502B1, 3-methylcholanthrene (3-MC) inducing P4501A1, and dexamethasone inducing two forms of P4503A. Induction is most effectively achieved by oral administration of the agents, and is rapid—aryl hydrocarbon hydroxylase (AHH) was increased within 1 h of administration of, for example, 3-MC. AHH, 7-ethoxycoumarin O-deethylase (ECOD), and 7-ethoxyresorufin O-deethylase (EROD) have been used most frequently as substrates to characterize intestinal P450s. Dietary factors affect intestinal P450s markedly—iron restriction rapidly decreased intestinal P450 to beneath detectable values; selenium deficiency acted similarly but was less effective; Brussels sprouts increased intestinal AHH activity 9.8-fold, ECOD activity 3.2-fold, and P450 1.9-fold; fried meat and dietary fat significantly increased intestinal EROD activity; a vitamin A-deficient diet increased, and a vitamin A-rich diet decreased intestinal P450 activities; and excess cholesterol in the diet increased intestinal P450 activity. The role of intestinal P450 in toxifying or detoxifying specific xenobiotics has been clearly demonstrated to only a limited extent. However, elevated intestinal P450 levels have been indirectly linked to gastrointestinal cancer. Intestinal metabolism of 2,2,2-trifluoroethanol produces intestinal lesions with consequent systemic bacterial infection.
ISSN:1040-8444
DOI:10.3109/10408449209089881
出版商:Taylor&Francis
年代:1992
数据来源: Taylor
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2. |
Evaluation of the Sensory Irritation Test for the Assessment of Occupational Health Risk |
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Critical Reviews in Toxicology,
Volume 21,
Issue 6,
1992,
Page 423-450
BosP. M. J.,
ZwartA.,
ReuzelP. G. J.,
BragtP. C.,
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摘要:
AbstractMany occupational exposure limits (OELs) are based on irritation. A sensory irritation test has been developed based on trigeminal nerve stimulation in the nasal mucosa of rodents which results in a decreased respiratory frequency. The RD50, the concentration inducing a 50% decrease in the respiratory rate, was proposed for the assessment of OELs. The reproducibility within one laboratory appeared to be satisfactory, but interlaboratory differences may be larger. Intra- and interspecies differences were inconsistent. Other effects (pulmonary irritation, toxicity) may interfere with trigeminal nerve stimulation. The effects of mixed and repeated exposures (the occurrence of“sensitization”and“(cross-)tolerance”) are evaluated. Severe toxicity was observed in animals exposed below the RD50for some compounds. A quantitative evaluation with respect to human data was not possible. The suitability of the test for the assessment of an OEL is doubted. The best purpose will be as an upper range-finding study for subacute or chronic toxicity experiments.
ISSN:1040-8444
DOI:10.3109/10408449209089882
出版商:Taylor&Francis
年代:1992
数据来源: Taylor
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3. |
Human Exposure to 2,3,7,8-TCDD and Risk of Cancer |
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Critical Reviews in Toxicology,
Volume 21,
Issue 6,
1992,
Page 451-463
JohnsonEric S.,
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摘要:
AbstractMost of the evidence for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans has centered around whether it causes malignant lymphomas (ML) and soft-tissue sarcomas (STS). A critical review of the literature indicates that the evidence does not support a causal role for TCDD in the etiology of ML. For STS, the evidence does not specifically incriminate TCDD either, although there is room for doubt. Cancers of other sites, particularly of the respiratory system and thyroid which were found to be statistically significantly in excess in either of the two largest studies of combined cohorts of occupationally exposed workers, were identified as candidate tumors for which a possible etiological role of TCDD might need investigation in future studies.
ISSN:1040-8444
DOI:10.3109/10408449209089883
出版商:Taylor&Francis
年代:1992
数据来源: Taylor
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4. |
The Pathogenesis of Organophosphate Polyneuropathy |
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Critical Reviews in Toxicology,
Volume 21,
Issue 6,
1992,
Page 465-487
LottiMarcello,
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摘要:
AbstractThis review discusses the facts regarding organophosphate-induced delayed polyneuropathy (OPIDP) as they are related to its pathogenesis rather than being a comprehensive review of all available data. Neuropathy target esterase (NTE) is considered to be the molecular target for OPIDP which is affected by several esterase inhibitors. Such inhibitors are ranked according to their toxicological effects as follows1. Phosphates, phosphoroamidates, and phosphonates cause OPIDP when high amounts of NTE are inhibited. In most cases 70 to 80% inhibition is enough, whereas in others much more is required.2. Phosphinates, carbamates, and sulfonyl halides cause either protection from or promotion of OPIDP when given before or after a neuropathic OP, respectively. Both effects are related to doses that inhibit NTE. Neuropathy is also caused by the combined treatment with a carbamate and a sulfonyl fluoride.The potency of a given NTE inhibitor to cause OPIDP is related to the chemistry of the residue left attached to NTE, in addition to its affinity for the enzyme. The capability of inhibited NTE to undergo the aging process distinguishes inhibitors with high from those with negligible or very low potency to cause OPIDP.Therefore, protection from neuropathic doses of effective OPs is obtained when NTE is mostly inhibited with nonageable inhibitors.Promotion of OPIDP is likely to involve another site besides NTE because it might occur when almost all NTE is affected. Promotion affects either progression or expression of OPIDP after the initial biochemical lesion on NTE. Since only NTE inhibitors have been proven to be promoters, it is possible that this site is made available after the initiation of OPIDP and that it may have biochemical properties indistinguishable from those of NTE of naïve birds.Age-related resistance to OPIDP also seems to be related to either progression or expression of OPIDP and/or to the different physiology of NTE at a given age. Previously reported resistance of rats to clinical OPIDP seems also to be age-dependent.The physiological function(s) of NTE is unknown, but some practical gains have been obtained from its identification, including OPIDP risk assessment and biomonitoring.
ISSN:1040-8444
DOI:10.3109/10408449209089884
出版商:Taylor&Francis
年代:1992
数据来源: Taylor
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