Species Differences In Susceptibility Research Articles

Use of lethal body burdens to indicate species differences in susceptibility to narcotic toxicants

Lethal body burdens (LBB) for 1,2- and 1,4-dihalogenated benzenes (F, Cl or Br) are determined in rainbow trout of two age-classes. LBBs range from 0.3 to 2.4 mmol/kg. There are no significant differences between the two tested age-classes of rainbow trout. The rainbow trout data are compared to LBBs for 1,2- and 1,4-difluorobenzene in fathead minnow which range from 2.7 to 3.0 mmol/kg, and to LBBs of dichloro- and dibromobenzenes in guppy and fathead minnow [Sijm et al. 1993] which range from 2.7 to 8.0 mmol/kg. Rainbow trout are more susceptible to dihalogenated benzenes than fathead minnow. The LBB can be used as an instrument to examine the intrinsic toxicity of a chemical to a species, and to indicate the susceptibility of a species. Possible reasons for differences in susceptibility among species are discussed.

Lung Lesions Induced by Continuous- and Pulsed-Wave (Diagnostic) Ultrasound in Mice, Rabbits, and Pigs

These studies documented the presence or absence of macroscopic and microscopic intraparenchymal hemorrhage in individual lung lobes of mice, rabbits, and pigs exposed to continuous- and pulsed-wave (diagnostic) ultrasound; we described the character of and lesions associated with the hemorrhage and compared differences in the lesions among species and exposure conditions to investigate the pathogenic mechanisms and species differences associated with ultrasound-induced lung hemorrhage. In a series of three sequential interdependent studies, 312 mice, 91 rabbits, and 74 pigs were divided at random into experimental groups and exposed to continuous-wave ultrasound (3 kHz modulated at 120 Hz) of acoustic pressure levels ranging from 0 to 490 kPa for 5, 10, or 20 minutes. In a fourth study, three mice, 43 rabbits, and six pigs were divided at random into experimental groups and exposed to pulsed-wave ultrasound (3- and 6-MHz center frequency) of peak rarefactional acoustic pressure levels ranging from 0 to 5.6 MPa for 5 minutes. Macroscopic lesions induced by continuous- and pulsed-wave ultrasound consisted of dark red to black areas of hemorrhage that extended from visceral pleural surfaces into lung parenchyma. Hemorrhage appeared spatially related to the edges of lung lobes where pleura of dorsal and ventral surfaces met, occurred in specific lung lobes in all three species, and appeared anatomically related to lung that was closest to and in contiguous alignment with the ultrasound transducer and thus the path of the sound beam. Macroscopic lesions were similar in all species under all exposure conditions for both continuous- and pulsed-wave ultrasound; however, hemorrhage was not induced in pig lung exposed to pulsed-wave ultrasound at any peak rarefactional acoustic pressure level. Eighteen mice (145 kPa exposure pressure), 60 rabbits (145-460 kPa exposure pressure), and 58 pigs (145-490 kPa exposure pressure) from study 3 were used for microscopic evaluation of lung exposed to continuous-wave ultrasound; three mice (6 MHz; 2.9 and 5.4 MPa), 39 rabbits (3 and 6 MHz; 2.3-5.4 MPa), and six pigs (3 and 6 MHz; 3.3, 5.4, and 5.6 MPa) from study 4 were used for microscopic evaluation of lung exposed to pulsed-wave ultrasound. Microscopic lesions and the character of hemorrhage induced by continuous-wave ultrasound were different from those induced by pulsed-wave ultrasound. Lesions induced by continuous-wave ultrasound under all exposure conditions were similar in all three species. Lesions induced by pulsed-wave ultrasound under all exposure conditions were similar in all three species.(ABSTRACT TRUNCATED AT 400 WORDS)

Effluent ecotoxicology in the wool-scouring process

The toxicity and biodegradation of several effluents from scouring of different types of wool were studied. Growth inhibition of a green freshwater algae species ( Chlorella vulgaris) was determined by the 201 OECD METHOD (72-h EC 50). Mobility inhibition of crustacean ( Daphnia magna) was determined as 24-h EC 50 by the 202 OECD method. Parameters such as total organic carbon (TOC), chemical oxygen demand (COD), 5-day biochemical oxygen demand (BOD 5) and biodegradation (D 28) were also studied. In this process, degradation of about 80% was achieved; therefore, these effluents were biodegradable, according to the 302 OECD method. All effluents affected the growth of C. vulgaris) and the mobility of D. magna. The highest toxicity of this effluent decreased upon centrifugation. The differences in species susceptibility to wool-scouring process effluents were usually small: less than a factor of 10 in most cases. No significant differences in the toxicity of various wool types from different origins were found. This could be because of the use of the same pesticides and/or a similar application pattern.

Antifungal susceptibility testing of Candida spp. by relative growth measurement at single concentrations of antifungal agents.

The relative growth (percentage of growth relative to control growth) of 496 isolates representing six Candida species was assessed as a means of determining in vitro susceptibilities of the isolates in microdilution plate wells containing single concentrations of each of seven antifungal agents. The relative growth data were highly reproducible. With flucytosine and amorolfine they correlated well with MICs, but for an azole antifungal agent, terconazole, they did not correlate with MICs. Distributions of relative growth percentages for different Candida spp. showed significant differences in species susceptibility to individual agents. For example, C. albicans was less susceptible than the other species to amorolfine; C. parapsilosis isolates were particularly susceptible to terbinafine; and C. glabrata, C. guilliermondii, and C. krusei isolates were less susceptible than C. albicans to fluconazole and ketoconazole but equally susceptible as or more susceptible than C. albicans to itraconazole. Differential patterns of susceptibility to individual azole antifungal agents were noted for some individual strains as well as for Candida spp.

Does the animal-to-human uncertainty factor incorporate interspecies differences in surface area?

Risk assessment practices for noncarcinogens typically employ an uncertainty factor (UF) for animal-to-human extrapolation when defining acceptable levels for humans based on animal studies. EPA has interpreted the use of this factor as addressing interspecies differences due to dose normalization via surface area (exposure-dose relationships) and to innate differences in species susceptibility (dose-response relationships). Thus EPA has concluded that dose normalization via surface area is not necessary when using animal studies to define acceptable levels for noncarcinogens for humans. In this report we challenge this position on both theoretical and practical grounds. It is recommended that the UF for animal-to-human extrapolation for noncarcinogens in the risk assessment process and the technique for dose normalization be considered distinctly.

Ecotoxicological risk evaluation of the cationic fabric softener DTDMAC. I. Ecotoxicological effects

The acute and (semi-) chronic toxicity of ditallow dimethyl ammonium chloride (DTDMAC) to several aquatic organisms was determined in surface water. The acute toxicity (96-h LC50) for the stickleback Gasterosteus aculeatus, the midge larva Chironomus riparius and the pond snail Lymnaea stagnalis was 4.5, 9.2 and 18 mg/l respectively. The NOECs determined in (semi-) chronic toxicity experiments with the same species were 0.75, 1.3 and 0.32 mg/l respectively. The NOEC for the green alga Scenedesmus pannonicus, the bacterium Photobacterium phosphoreum (Microtox) and nitrifying bacteria was 0.75, 5.6 and 3 mg/l, respectively. From these results it can be concluded that DTDMAC is a rather toxic chemical and differences in species susceptibility to DTDMAC are small.

Growth and resistance to herbivory in N2-fixing alders

Fixation of atmospheric N2 may provide an advantage to woody plants in N-limited environments, but may also alter their resistance to herbivory. Studies in adjacent plantings of three North American shrub alders (Alnus spp.) and three Eurasian tree alders showed significant species differences in susceptibility to a leaf-mining sawfly (Fenusa dohrnii) and in response to inoculation with a N2-fixing actinomycete (Frankia). During the first 5 years, woody biomass production ranged from 0.3 t∙ha−1∙year−1 in Alnus viridis ssp. sinuata (Sitka alder) to 8.3 t∙ha−1∙year−1 in Alnus incana ssp. incana (grey alder). Grey alder and another tree species (Alnus japonica) were attacked infrequently and suffered little sawfly damage except in plots with poor growth. The tree species Alnus glutinosa (black alder) was attacked frequently, and sawfly damage was greatest in plots with the best growth. The shrub species Alnus viridis ssp. crispa (green alder) was also attacked frequently but was highly resistant to larval feeding. Frequently attacked species showed greater damage in the lower portion of the crown. Frankia inoculation increased green alder biomass by 87% but had no significant effect on grey alder or black alder. The concept of a growth-defense trade-off does not fully explain the interactions between Alnus spp. and F. dohrnii. Key words: Alnus, Fenusa dohrnii, Frankia, biomass production, plant–herbivore interactions, leaf miner.

Species differences in susceptibility to 1,3-dinitrobenzene-induced testicular toxicity and methemoglobinemia

The testicular toxicity and methemoglobinemia induced by 1,3-dinitrobenzene (1,3-DNB) was compared in two species, the Sprague-Dawley rat and the golden Syrian hamster. A marked difference in susceptibility to both endpoints of toxicity was observed. The hamster showed no testicular lesions at dose levels up to 50 mg/kg whereas, as previously reported by others, damage to rat testicular tubules in later stages of spermatogenesis was readily apparent at a 25 mg/kg dose level. Similarly, administration of 1,3-DNB induced substantially less methemoglobinemia in the hamster than in the rat. For example, at the 25 mg/kg dose level peak levels of methemoglobin in the hamster were 15% compared with 80% in the rat. Mortality in the rat also occurred at lower doses than in the hamster (50 vs 100 mg/kg, respectively). In in vitro studies, the capacity of 1,3-DNB and 1,3-DNB metabolites (nitroaniline, nitroacetanilide, aminoacetanilide, diacetamidobenzene) to induce methemoglobinemia was examined in suspensions of red blood cells obtained from both species. Only 1,3-DNB caused the formation of methemoglobin and rat red blood cells were twice as sensitive as hamster red blood cells. The species difference in susceptibility to both methemoglobinemia and testicular toxicity could indicate differences in 1,3-DNB clearance and/or formation of toxic metabolites. Additional metabolic work is under way. This study demonstrates that the hamster is more resistant than the rat to the testicular lesion and methemoglobinemia induced by 1,3-DNB.

Species Differences in Susceptibility to 1,3-Dinitrobenzene-lnduced Testicular Toxicity and Methemoglobinemia

The testicular toxicity and methemoglobinemia induced by 1,3-dinitro-benzene (1,3-DNB) was compared in two species, the Sprague-Dawley rat and the golden Syrian hamster. A marked difference in susceptibility to both endpoints of toxicity was observed. The hamster showed no testicular lesions at dose levels up to 50 mg/kg whereas, as previously reported by others, damage to rat testicular tubules in later stages of spermatogenesis was readily apparent at a 25 mg/kg dose level. Similarly, administration of 1,3-DNB induced substantially less methemoglobinemia in the hamster than in the rat. For example, at the 25 mg/kg dose level peak levels of methemoglobin in the hamster were 15% compared with 80% in the rat. Mortality in the rat also occurred at lower doses than in the hamster (50 vs 100 mg/kg, respectively). In in vitrostudies, the capacity of 1,3-DNB and 1,3-DNB metabolites (nitroaniline, nitroacetanilide, aminoacetanilide, diacetamidobenzene) to induce methemoglobinemia was examined in suspensions of red blood cells obtained from both species. Only 1,3-DNB caused the formation of methemoglobin and rat red blood cells were twice as sensitive as hamster red blood cells. The species difference in susceptibility to both methemoglobinemia and testicular toxicity could indicate differences in 1,3-DNB clearance and/or formation of toxic metabolites. Additional metabolic work is under way. This study demonstrates that the hamster is more resistant than the rat to the testicular lesion and methemoglobinemia induced by 1,3-DNB. c 1991 Society of Toxicoiofy.

Species Differences in the Infectability of Vascular Grafts

The susceptibility of different species to bacteremia may influence the results of studies on vascular graft infection. The present study compares prosthetic graft infection in canine and porcine models. Thirty-four mongrel dogs and 38 Yorkshire pigs underwent replacement of the infrarenal aorta with a 3-cm segment of a woven Dacron prosthesis. At the time of closure, each animal received an intravenous inoculum of 10(2) to 10(8) Staphylococcus aureus (S. aureus). Graft cultures at 1 week produced a predictable infection rate in dogs, while pigs developed only random infections (dogs: 23/34; pigs: 7/38; p = .0001). The median infective dose (ID50) in dogs was 10(2.9) but pigs did not develop enough infections to determine this value. Electron microscopy revealed a smooth fibrin surface in grafts explanted from pigs, while grafts from dogs demonstrated bacteria enmeshed in an irregular fibrinous lining. Prosthetic vascular grafts in dogs are more susceptible to hematogenous infection than those in pigs. Because hematogenous infection in humans is a rare event, the swine model may be a more appropriate representation of the clinical situation.

Species differences in renal γ-glutamyl transpeptidase activity do not correlate with susceptibility to 2-bromo-(diglutathion- S-yl)-hydroquinone nephrotoxicity

Administration of 2-brono-(diglutathion- S-yl)hydroquinone (2-Br-[diGSyl]HQ) 1 (10–30 μmol/kg; i.v.) to rats causes severe renal proximal tubular necrosis. γ-Glutamyl transpeptidase (γ-GT) catalyses the first step in the metabolism of glutathione (GSH) and its S-conjugates and the toxicity of 2-Br-(diGSyl) HQ can be emeliorated by inhibition of renal γ-GT. Species differences in the specific activity of renal γ-GT have been reported and we now describe the relationship between renal γ-GT and species differences in susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although rats exhibited the highest specific activity of renal γ-GT, and were the most sensitive species toward 2-Br-(diGSyl)HQ-mediated nephrotoxicity, renal γ-GT activity did not correlate with susceptibility in the other species examined. Indeed, the guinea pig, which expressed the lowest activity of renal γ-GT between the species (8% of the rat) was the only other rodent found to be responsive toward 2-Br-(dGSyl)HQ at the highest dose tested (200 μmol/kg; intracardiac). Thus, factors other than γ-GT activity probably play an important role in modulating species susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although the reason(s) for the interspecies variation in response to 2-Br-(diGSyl)HQ are unclear at present, it seems possible that differences in both renal biochemistry, such as differences in the relative activities of cysteine conjugate N-acetyl transferase and deacetylase, and renal physiology, contribute to the observed results.

Aneuploidy induction in human fibroblasts: comparison with results in Syrian hamster fibroblasts

The susceptibility of human fibroblast cells in culture to neoplastic transformation by chemical carcinogens is appreciably lower than that of rodent fibroblasts. We have proposed that a key step in the neoplastic progression of Syrian hamster embryo fibroblasts is the induction of aneuploidy by carcinogens. It is possible that the different sensitivity to neoplastic transformation of Syrian hamster versus human cells is due to a difference in genetic stability following treatment with chemicals inducing aneuploidy. Therefore, we measured the induction of numerical chromosome changes in normal human fibroblasts and Syrian hamster fibroblasts by 4 specific aneuploidogens. Dose- and time-dependent studies were performed. Nondisjunction, resulting in aneuploid cells with a near-diploid chromosome number, in up to 14–28% of the hamster cells was induced by colcemid (0.1 μg/ml), vincristine (30 ng/ml), diethylstilbestrol (DES) (1 μg/ml) or 17β-estradiol (10 μg/ml). In contrast, human cells displayed far fewer aneuploid (near-diploid) cells, i.e., 8% following treatment with colcemid (0.02 μg/ml) or vincristine (10 ng/ml) and only 3% following treatment with DES (6 μg/ml) or 17β-estradiol (20 μg/ml). The doses at which the maximum effect was observed are given. Treatment of human cells induced a higher incidence of cells with a near-tetraploid chromosome number, which was similar to the level observed in treated hamster cells except at the highest doses. These results indicate that human cells respond differently from hamster cells to agents that induce aneuploidy. In particular, nondisjunction yielding aneuploid human fibroblasts with a near-diploid chromosome number was less frequent. The magnitude of the observed species differences varied with different chemicals. The difference in aneuploidy induction may contribute, in part, to species differences in susceptibility of fibroblasts to neoplastic transformation.

The liver slice system: A rapid in vitro acute toxicity test for primary screening of hepatotoxic agents

A simple method for the rapid screening of hepatotoxic agents is described. Liver slice systems were prepared from rats and mice, and incubated in Krebs-Ringer-Hepes medium with different concentrations of the test compounds. Hepatotoxicity was monitored by determination of liver enzymes in the slice medium. Enzyme leakage was dose- and time-dependent. Histopathological changes in the hepatotoxin-treated slices were well correlated with the extent of enzyme leakage. Species differences in susceptibility to various hepatotoxins could be easily detected by this in vitro system: the dose-toxicity curves revealed that the mouse is more vulnerable than the rat to acetaminophen and furosemide. These findings are well correlated with those of in vivo experiments. A preliminary study showed that, in the same species, the relative toxicities of various chemicals in the liver slice system were similar to those reported in vivo. In summary, these results on the tissue slice system are encouraging. However, much more work will have to be done before the system can be considered sufficiently well validated for routine use.

The Different Genotoxicity of P-Dichlorobenzene in Mouse and Rat: Measurement of the in Vivo and in Vitro Covalent Interaction with Nucleic Acids

Twenty-two hours after i.p. injection to male Wistar rats and BALB/c mice para-dichlorobenzene (p-DCB) is bound covalently to DNA from liver, kidney, lung and stomach of mice but not of rats. DNA adducts in mouse liver are repaired in seventy-two hours. The covalent binding index value, calculated on the labelling of mouse liver DNA, classifies p-DCB as a weak initiator with an oncogenic activity lower than that of chlorobenzene. The labelling of RNA and proteins from the different organs of both species is, however, low. In vitro interaction with calf thymus DNA mediated by mouse and rat microsomes from liver and lung did occur. Binding extent was strongly reduced by addition of 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A) to the microsomal standard incubation mixture, whereas it was enhanced by adding GSH. Cytosolic fractions from kidney and lung were able to induce binding of p-DCB to DNA to a lower extent with respect to microsome-mediated binding. These results indicate that microsomal mixed function oxidase system and microsomal GSH-transferases can be involved in overall activating metabolism whereas cytosolic GSH-transferases play a minor role. This study, which is a part of a structure-activity relationship approach on benzene and its haloderivatives, provides the first evidence of genotoxicity of p-DCB in mammalian cell. It allows to partly explain variations of susceptibility of different species to hepatocarcinogenesis and of hepatotoxicity of different isomers.

Isolation and identification of 3-hydroxy-3-methyloxindole, the major murine metabolite of 3-methylindole

3-Methylindole (3MI) is pneumotoxic to ruminants and rodents subsequent to metabolic oxidative activation by cytochrome P-450 monooxygenases. Goats are much more susceptible than mice and rats to 3MI-mediated lung damage, and these differences in species susceptibility may be reflected by differences in the metabolic products of 3MI. Radioactive 3MI was administered ip to Swiss-Webster mice, and the major nonpolar urinary metabolites were fractionated and separated by HPLC. Although 3-methyloxindole has been shown to be the major urinary metabolite of 3MI in goats, it was not detected in mouse urine. Instead, the major metabolite, 3-hydroxy-3-methyloxindole, was isolated and purified and its structure elucidated by 1H and 13C NMR, mass spectrometry, and IR spectroscopy. This is the first identification of this highly oxidized indole from mammalian sources. The production of this metabolite may be indicative of the formation of an electrophilic methyleneoxindole intermediate, which could be responsible for pneumotoxicity in this species.

Comparative metabolism of benzo[a]pyrene and (−)benzo[a]pyrene-7,8-dihydrodiol by hepatocytes isolated from two species of bottom-dwelling fish

In order to elucidate the biochemical bases of species differences in susceptibility to hepatotumorigenesis induced by polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BP), we investigated the metabolism of [ 3H]BP and its proximate carcinogenic metabolite (−)BP-7,8-dihydrodiol (BP-7,8-diol) by two benthic fish: brown bullheads ( Ictalurus nebulosus) (a susceptible species) and mirror carp ( Cyprinus carpio) (not known to be susceptible). Freshly isolated hepatocytes prepared from both species efficiently converted both BP and BP-7,8-diol (the proximate carcinogenic metabolite of BP) to glutathione conjugates, glucuronides and sulfates and polyhydroxylated compounds. Nevertheless, carp hepatocytes (which metabolized both BP and BP-7,8-diol about 2-fold faster than did bullhead hepatocytes) produced several-fold larger amounts of DNA adducts from both substrates, suggesting the formation by carp liver of significantly larger amounts of reactive intermediates that bind to DNA. The apparently greater susceptibility of brown bullheads to PAH-induced carcinogenesis thus awaits further clarification.

Effects of modulation of hepatic glutathione on biotransformation and covalent binding of aflatoxin B 1 to DNA in the mouse

Relative to the rat and most other species tested, the mouse is resistant to the carcinogenic effets of aflatoxin B 1 (AFB). Previous in vestigations in our laboratory demonstrated that mouse liver cytosol has 52 times greater hepatic glutathione S-transferase (GST) activity toward the AFB-epoxide, compared with rat liver cytosol. To determine the importance of GST-mediated detoxification of the AFB-epoxide in the mouse in vivo, we examined the effects of glutathione (GSH) depletion on the covalent binding of AFB to hepatic DNA in control and 2(3)-butyl-4-hydroxyanisole (BHA)-treated mice. Male Swiss-Webster mice were fed control or 0.75% BHA diet for 14 days. Depletion of hepatic GSH was accomplished with d,l-buthionine- S-sulfoximine (BSO, 0.6 g/kg in saline) and diethyl maleate (DEM, 0.75 ml/kg), administered by ip injection at 2 and 1.5 hr, respectively, prior to administration of 3H-AFB (0.25 mg/kg, ip in DMSO). The combined BSO-DEM treatment depleted hepatic GSH by 97 and 70% in control and BHA-treated mice, respectively. In mice receiving the control diet, GSH depletion was associated with a 30-fold increase in the covalent binding of AFB to hepatic DNA. AFB-DNA binding in mice treated with dietary BHA alone was reduced to 54% of control. In BHA-treated mice, BSO-DEM treatment increased AFB-DNA binding by 62%. Dietary BHA increased hepatic S-9 mediated activation of AFB to the AFB-epoxide by eightfold in both control and BSO-DEM mice. BHA also increased GST activity toward the AFB-epoxide by 52 and 68% in control and BSO-DEM mice, respectively. The BSO-DEM treatment alone had no significant effect on the in vitro biotransformation of AFB. These results support the hypothesis that GST is the pricipal determinant of species differences in susceptibility to AFB-induced hepatocarcinogenicity. The results also support the hypothesis that BHA may protect against the toxic and carcinogenic effects of xenobiotics in part by preventing the depletion of hepatic GSH.

Experimental toxicology of formaldehyde.

Formaldehyde is a reactive chemical which undergoes spontaneous reactions with various cellular constituents. Mutagenicity data may be interpreted on the background of this behavior. Mice are better able to reduce the irritating effect of formaldehyde than rats and to reduce their ventilation rate when formaldehyde acts on the respiratory tract. Subacute exposure of rats to concentrations higher than 2 ppm inhibits mucociliary clearance of the nasal epithelium and leads to progressive histological and ultrastructural lesions at this site. The occurrence of squamous cell carcinomas of the nasal epithelium of rats after 2 years inhalation of 14.3 ppm formaldehyde (CIIT study) is probably the result of chronic and recurrent local toxicity; this is supported by species differences in susceptibility to the tissue damaging and carcinogenic effect of formaldehyde (rat, mouse, hamster). Data on formaldehyde-DNA interaction further support the argument that a direct risk extrapolation from the formaldehyde effects in rats to those expected for man is not possible.

Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, we hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. We tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of [3H]pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. [3H]Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of "enzyme barriers" at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson disease.

Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.

Susceptibility to oxygen toxicity was studied in three inbred and two hybrid strains of mice. Because in vitro studies have shown that the cytochrome P-450 enzymes can produce oxygen radicals and H2O2, we tested the hypothesis that inducibility of these enzymes might play a role in oxygen toxicity. Mice responsive to hepatic microsomal enzyme induction by aromatic hydrocarbons [C3H/HeJ, C3H/HeN, C3H/HeJ X DBA/2J (designated C3D2F1/J), C3H/HeN X DBA/2J (designated C3D2F1/N)] were more sensitive to the toxic effects of 100% oxygen exposure than were genetically unresponsive mice (DBA/2J). DBA/2J mice survived significantly longer exposure periods with less lung damage. Lung and liver cytochrome P-450 levels increased 2-to 3-fold in C3H and F1 mice during 100% oxygen exposure (maximum levels at 72-96 hr) and subsequently fell prior to death. No increases were seen in cytochrome P-450 levels in DBA/2J mice. Metabolic pathways involving cytochrome P-450 enzymes may initiate or modulate oxidative damage due to oxygen radicals. The difference in responsiveness of mice to microsomal enzyme induction may imply genetic differences in susceptibility to oxidative stress, may help to explain species differences in susceptibility, and may have long-term implications in therapeutics and patient care if similar inherited differences exist in humans.