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Although structurally related to other steroid thyroid hormone nuclear receptors, Nur77, Nurr1 and NOR-1 represent a distinct subfamily of nuclear receptors, the Nur77 receptor subfamily. In addition to very strong structural homologies among these three nuclear receptors, all can be rapidly induced as immediate early genes. Furthermore, they have similar DNA binding and transactivation properties, and can function in the absence of a not yet known ligand(s). The present review addresses the properties of the Nur77 receptor subfamily, including gene structure, promotor elements, regulation of expression, DNA binding and transactivation properties, and potential physiological and developmental roles. The functions of all three receptors in negative selection of T-cells, the regulation of the hypothalamus-pituitary-adrenal axis and the potential functional redundancy are discussed. Also reviewed is the role of Nurr1 in the differentiation and function of midbrain dopaminergic neurons, as demonstra ted by the ablation of Nurr1 function in mice, and the potential implications for Nurr1 in Parkinsons disease and or schizophrenia. Although similar in many structural and functional aspects, subtle differences in certain properties, regulation and expression patterns of the different receptors may result in different physiological roles of these proteins, while similarities may account for a redundancy of function. Much has been described about the regulation of these proteins, however, future research will need to focus on the identification of potential ligands and the target genes that are regulated by this unique class of transcription factors.

Formic acid is the toxic metabolite responsible for the retinal and optic nerve toxicity produced in methanol intoxication. Previous studies in our laboratory have documented formate-induced retinal dysfunction and histopathology in a rodent model of methanol intoxication. The present studies define the time and concentration dependence of formate-induced retinal toxicity in methanol-intoxicated rats. Retinal function was assessed 24, 48, and 72 h after the initial dose of methanol by flicker electroretinographic measurements. Retinal histopathology was assessed at the same time intervals. Rod- and cone-mediated electroretinogram (ERG) responses were attenuated in a formate concentration- and time-dependent manner, and both retinal sensitivity and maximal responsiveness to light were diminished. Attenuation of UV-cone-mediated responses was temporally delayed in comparison to the functional deficits observed in the 15 Hz/510 nm responses, which have a rod-mediated component and occurred at significantly higher formate concentrations. Both 15 Hz/510 nm and UV-cone-mediated ERG responses were undetectable by 72 h; however, if light intensity was increased, a retinal ERG response could be recorded, indicating that photoreceptor function was profoundly attenuated, but not abolished, under these intoxication conditions. Functional changes preceded structural alterations. Histopathological changes were most pronounced in the outer retina with evidence of inner segment swelling, photoreceptor mitochondrial disruption, and the appearance of fragmented photoreceptor nuclei in the outer nuclear layer. The nature of both the functional and structural alterations observed are consistent with formate-induced inhibition of mitochondrial energy production, resulting in photoreceptor dysfunction and pathology.

The susceptibility of various species to methanol toxicity is inversely related to the rate of tetrahydrofolate (H4folate)-dependent formate oxidation to carbon dioxide. Thus, the levels of various folate derivatives and folate-dependent enzyme activities present in the livers of monkeys, which are sensitive to methanol, and rats, which are not, were compared in order to investigate the biochemical basis of this species difference. Hepatic H4folate levels in monkeys were 60% of those in rats, and formylated-H4folate derivatives were 2-fold higher in monkeys than in rats. No significant difference between monkeys and rats in the levels of total hepatic folate or 5-methyl-H4folate was observed. The activities of formyl-H4folate synthetase (EC 6.3.4.3) and formyl-H4folate dehydrogenase (EC 1.5.1.6) were 4- and 2-fold higher, respectively, in monkeys than in rats. There was no significant difference between monkeys and rats in methionine synthetase activity (EC 2.1.1.13). Dihydrofolate reductase activity (EC 1.5.1.3) in monkeys was 20% of that in rats. 5,10-Methylene-H4folate reductase (NADPH) activity (EC 1.1.1.171) in monkeys was 40% and 25% of that in rats when the rates of the forward and reverse reactions, respectively, were compared. Serine hydroxymethyltransferase activity (EC 2.1.2.1) was 2-fold higher in monkeys than in rats. The differences in the activities of methylene-H4folate reductase and serine hydroxymethyl-transferase between monkeys and rats may have contributed to the difference in hepatic H4folate levels. The 40% lower level of hepatic H4folate in monkeys, as compared to rats, relates well to the 50% lower maximal rate of formate oxidation in monkeys. Thus, the species difference in susceptibility to methanol may be explained by the difference in the level of hepatic H4folate.

The neuroexcitatory actions of two toxicologically distinct classes of pyrethroid insecticides were characterized in rat brain synaptosomes using [3H]tetraphenylphosphonium to measure changes in synaptosomal membrane potential and by measuring the release of [3H]acetylcholine. Both type I (permethrin) and type II (deltamethrin, cypermethrin and fenvalerate) pyrethroids produced a concentration-dependent tetrodotoxin-sensitive membrane depolarization which was stereospecific for the neurotoxic isomer of each pyrethroid. Deltamethrin was the most potent and efficacious pyrethroid in these studies, with an EC50 of 30 nM and a maximal estimated membrane depolarization of 27 mV, followed by cypermethrin, fenvalerate and permethrin. The phenoxybenzyl pyrethroids also increased the spontaneous release of [3H]acetylcholine from rat brain synaptosomes, further supporting a depolarizing action of these insecticides on nerve terminal membranes. Pyrethroid-induced release of [3H]acetylcholine was tetrodotoxin-sensitive and occurred over the same concentration range as membrane depolarization. These data indicate that type I and type II phenoxybenzyl pyrethroids act potently and stereoselectively on the voltage-sensitive sodium channel to increase sodium influx into synaptic terminals producing membrane depolarization and neurotransmitter release. Furthermore, they show that pyrethroid-induced alterations in synaptosomal membrane potential is a sensitive measure of pyrethroid action on the sodium channel and of pyrethroid toxicity.

Human methanol poisoning is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are ordinarily resistant to the accumulation of formate and the associated metabolic and visual toxicity. A nonprimate model of methanol-induced visual toxicity was developed using rats treated with subanesthetic concentrations of nitrous oxide to inhibit the oxidation of methanol's toxic metabolite, formic acid. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity within 36 hr of methanol administration analogous to the human methanol poisoning syndrome. Visual dysfunction was measured as reductions in the flash-evoked cortical potential and electroretinogram, which occurred coincident with blood formate accumulation. Alterations in the electroretinogram occurred at formate concentrations lower than those associated with other visual changes and provide functional evidence of direct retinal toxicity in methanol poisoning.

Formic acid does not accumulate in the rat after the administration of methanol as it does in methanol-poisoned humans and monkeys. In addition, rats do not manifest the metabolic acidosis and ocular toxicity characteristic of methanol intoxication in primates. Nitrous oxide treatment was used to inhibit 5-methyltetrahydrofolate homocysteine methyltransferase (methionine synthetase, EC 4.2.99.10) in order to delineate the role of this enzyme in regulating the metabolism of formate in rats and in determining the sensitivity of this species to methanol intoxication. Nitrous oxide treatment resulted in a decrease in hepatic levels of nonmethylated tetrahydrofolate forms and an increase in 5-methyltetrahydrofolate. Rats treated with nitrous oxide exhibited a marked decrease in the rate of oxidation of formate to carbon dioxide. The rate of disappearance of formate from the blood in these animals was decreased to half the control rate. Rats treated with nitrous oxide and administered methanol accumulated formate in blood and developed metabolic acidosis. These studies support the concept of a key role of methionine synthetase in supplying the tetrahydrofolate required for the folate-dependent oxidation of formate to carbon dioxide as well as the importance of this pathway in determining the sensitivity of a species to methanol poisoning.

After methanol administration to monkeys, an accumulation of formate in blood occurs coincident with the development of metabolic acidosis and a depletion of blood bicarbonate. Formate metabolism in monkeys depends upon and is regulated by a folate‐dependent system; therefore, the effect of folic acid pretreatment and 5‐formyl tetrahydrofolic acid administration on methanol toxicity was investigated. Treatment of monkeys with repetitive doses of either sodium folate (48, 24, 12, and 4 hr prior to methanol) or 5‐formyl tetrahydrofolic acid (2 mg/kg at 0, 4, 8, 12, and 18 hr after methanol) resulted in a marked decrease in the levels of blood formate and an absence of both metabolic acidosis and depletion of blood bicarbonate following methanol administration. Also, 5‐formyl tetrahydrofolic acid reversed methanol toxicity once it was established in the monkey. The results indicate that folate compounds decrease formate accumulation after methanol by stimulating formate oxidation or utilization and suggest a possible use for folates in the treatment of certain cases of human methanol poisoning.

The effects of the synthetic pyrethroid insecticide fenvalerate ([R,S]-alpha-cyano-3-phenoxybenzyl[R,S]-2-(4-chlorophenyl)-3- methylbutyrate) on neurotransmitter release in rabbit brain slices were investigated. Fenvalerate evoked a calcium-dependent release of [3H]dopamine and [3H]acetylcholine from rabbit striatal slices that was concentration-dependent and specific for the toxic stereoisomer of the insecticide. The release of [3H]dopamine and [3H]acetylcholine by fenvalerate was modulated by D2 dopamine receptor activation and antagonized completely by the sodium channel blocker, tetrodotoxin. These findings are consistent with an action of fenvalerate on the voltage-dependent sodium channels of the presynaptic membrane resulting in membrane depolarization, and the release of dopamine and acetylcholine by a calcium-dependent exocytotic process. In contrast to results obtained in striatal slices, fenvalerate did not elicit the release of [3H]norepinephrine or [3H]acetylcholine from rabbit hippocampal slices indicative of regional differences in sensitivity to type II pyrethroid actions.

Methanol poisoning in monkeys and humans is characterized by the development of formic acidemia, metabolic acidosis and ocular toxicity. Formate, the metabolite associated with the toxicity of methanol, is oxidized to carbon dioxide by a tetrahydrofolate-dependent pathway. Nitrous oxide treatment was used to inhibit the tetrahydrofolate-generating enzyme, 5-methyltetrahydrofolate homocysteine methyltransferase (methionine synthetase, E.C. 2.1.1.13.), to delineate the role of this enzyme in regulating formate oxidation in the monkey. The importance of methionine in the regulation of formate oxidation in the monkey also was evaluated. Nitrous oxide inhibited the oxidation of formate generated from the metabolism of methanol (1 g/kg i.p.) in the monkey, resulting in the development of severe metabolic acidosis and high blood formate levels in these animals compared with air-breathing monkeys administered the same dose of methanol. Treatment of nitrous oxide-exposed monkeys with repetitive doses of methionine (100 mg/kg 10, 12 and 14 hr after methanol) reversed the effects of nitrous oxide on formate oxidation, resulting in a marked decrease in blood formate levels and an increase in the rate of [14C]O2 formation from methanol. Methionine treatment also reversed the development of metabolic acidosis and bicarbonate depletion observed in nitrous oxide-exposed monkeys. These results indicate that hepatic methionine synthetase is important in the regulation of tetrahydrofolate-dependent metabolism in the monkey and that the generation of tetrahydrofolate by this enzyme is a major factor in determining the sensitivity of a species to methanol poisoning.

ByH. Grauertand R. Remmert: pp. 249. DM.79,50; US$43.80. (Springer‐Verlag, 1979.)

ByIsaacChavel: pp. 362. £46.50, US$62.00 (Academic Press Inc, U.S.A., 1984.)

ByStanisław Łojasiewicz: 537 pp., DM.198.‐, ISBN 3 7643 1935 6 (Birkhäuser, 1991).

ByDanielS. Freedand KarenK. Uhlenbeck: pp. 232. DM48–; US$17.50. (Springer‐Verlag, Berlin, 1984.)

ByBruceL. Reinhartpp. 195. DM.98‐; US$40.50. (Springer‐Verlag, 1983.)

ByN. G. Lloyd: pp. 172. £8.50. (Cambridge University Press, 1978).

ByShiing‐ShenChern: pp. 152. DM.24,—, US$13.20. (Springer‐Verlag, 1979).

ByJerry L. Kazdan: pp. 55. US$12.00. (American Mathematical Society, 1985.)

ByEnrico Bombieri: pp. 99. US$25.00. (Harwood Academic Publishers, 1985).

ByT. Aubin: pp. 204. DM.79‐; US$32.70. (Springer‐Verlag, Berlin, 1982.)

Mitochondria have long been known to participate in the process of cell injury associated with metabolic failure. Only recently, however, have we come to appreciate the role of mitochondria as primary intracellular targets in the initiation of cell dysfunction. In addition to ATP synthesis, mitochondria are also critical to modulation of cell redox status, osmotic regulation, pH control, and cytosolic calcium homeostasis and cell signaling. Mitochondria are susceptible to damage by oxidants, electrophiles, and lipophilic cations and weak acids. Chemical-induced mitochondrial dysfunction may be manifested as diverse bioenergetic disorders and considerable effort is required to distinguish between mechanisms involving critical mitochondrial targets and those in which mitochondrial dysfunction is secondary and plays only a modulatory role in cell injury. The following paragraphs review a few important examples of chemical-induced cytotoxic responses that are manifested as interference with mitochondrial metabolism and bioenergetics, gene regulation, or signal transduction in the form of apoptosis and altered cell cycle control. Greater understanding of the molecular mechanisms of mitochondrial bioenergetics, ion regulation, and genetics will lead to numerous additional examples of mitochondria-mediated cell injury, revealing important new insight regarding the prediction, prevention, diagnosis, and treatment of chemical-induced toxic tissue injury.