Retinol Pretreatment Research Articles

Effect of Applying Various Time of Retinol Pretreatment on Improve Skin after Herbal Peeling

ëª©ì  본 연구의 ëª©ì ì€ 약초필링 ì´ì „ì— 기간이 다른 ë ˆí‹°ë†€ ì „ì²˜ë¦¬ê°€ 필링 후 발생하는 부작용을 ìµœì†Œí™”í•˜ê³ í”¼ë¶€ ê°œì„ íš¨ê³¼ë¥¼ ê²€ì¦í•˜ê³ ìž 하였다. 방법 약초필링 ì „ ë ˆí‹°ë†€ë¡œ ì „ì²˜ë¦¬ 하지 않은 그룹을 Group 1 (G1, 대조군), ì•½ì´ˆí•„ë§ì „ 4주간(8주-12주) ë ˆí‹°ë†€ë¡œ ì „ì²˜ë¦¬í•œ 그룹을 Group 2 (G2), ì•½ì´ˆí•„ë§ì „ 8주간(4주-12주) ë ˆí‹°ë†€ë¡œ ì „ì²˜ë¦¬í•œ 그룹을 Group 3 (G3), 약초필링 ì „ 12주간(1주-12주) ë ˆí‹°ë†€ë¡œ ì „ì²˜ë¦¬í•œ 그룹을 Group 4 (G4)로 하였다. 연구기간은 총 15주간 진행되었는데, í•„ë§ì „ ë ˆí‹°ë†€ ì „ì²˜ë¦¬ 기간 ì‹œìž‘ì ì„ 달리하여 G 4는 첫 주부터, G 3은 4주째부터, G 2은 8주째부터 ë ˆí‹°ë†€ ì ìš© 홈케어를 하였다. 실험 ì „, 13주차(필링 1 주일) 및 15주차(필링 2 주 후)의 피부 홍반 지수, 수분 함량, TEWL 및 ê±°ì¹ ê¸°ë¥¼ ì¸¡ì •í•˜ì˜€ë‹¤. ê²°ê³¼ 본 연구를 통해 기간이 다른 ë ˆí‹°ë†€ ì „ì²˜ë¦¬ê°€ 수분증가와 홍반, TEWL 및 ê±°ì¹ ê¸°ì˜ 감소를 í™•ì¸í• ìˆ˜ 있었다. ë ˆí‹°ë†€ ì „ì²˜ë¦¬ 그룹은 ë¯¸ì „ì²˜ë¦¬ 그룹보다 홍반이 낮으며, ìœ ì˜í•œ 차이가 있는 것으로 나타났다. 또한 ë ˆí‹°ë†€ ì „ì²˜ë¦¬ 그룹은 ë¯¸ì „ì²˜ë¦¬ 그룹보다 보습이 높았으며, ìœ ì˜í•œ 차이가 있는 것으로 나타났다. ë ˆí‹°ë†€ ì „ì²˜ë¦¬ 그룹은 ë¯¸ì „ì²˜ë¦¬ 그룹보다 TEWL 및 ê±°ì¹ ê¸°ê°€ 낮았을 뿐만 아니라 ìœ ì˜í•œ 차이가 있는 것으로 밝혀졌다. 홍반, 수분, TEWL, ê±°ì¹ ê¸°ì—ì„œ G4는 G3보다 더 큰 변화가 ìžˆì—ˆê³ G3은 G2보다 더 컸다. 따라서 ìž¥ê¸°ì ì¸ ë ˆí‹°ë†€ ì „ì²˜ë¦¬ 그룹은 홍반, 탈수, 피부 자극 ê°œì„ ë° 완화에 ê¸ì •ì ì¸ 효과가 있는 것으로 확인됐다. ê²°ë¡ ì´ìƒì˜ 결과를 바탕으로 필링 ì „ 기간을 달리한 ë ˆí‹°ë†€ ì „ì²˜ë¦¬ëŠ” 기간이 ì¦ê°€í• ìˆ˜ë¡ 홍반, 수분 부족, 피부자극증상을 ê°œì„ , 완화하는데 있어 ê¸ì •ì ì¸ 효과를 나타내므로, 향후 피부 ê°œì„ ì— 가장 íš¨ê³¼ì ì¸ ì „ì²˜ë¦¬ë¡œì¨ì˜ ë ˆí‹°ë†€ 함량에 따른 ì œì œì˜ ì•ˆì •ì„±, 사용기간에 관한 연구가 좀 더 ë‹¤ì–‘í•˜ê³ í­ë„“ê²Œ 진행되어 필링 ì „ ì „ì²˜ë¦¬ 프로그램으로써 대중화가 ë ìˆ˜ 있도록 ì ê·¹ 활용되기를 기대한다. 핵심용어: ë ˆí‹°ë†€, ì „ì²˜ë¦¬, 다양한 시간, 약초필링, 피부개ì„

Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion

Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver.

Characterization of the effect of retinol on Plasmodium falciparum in vitro

A preliminary study from our laboratory found retinol (vitamin A alcohol) to have in vitro activity against Plasmodium falciparum at concentrations close to those in normal human serum (1–3 μM). To characterize the antimalarial potential of retinol in more detail, the 3D7 and K1 laboratory strains of P. falciparum were maintained in continuous culture and [ 3H]hypoxanthine incorporation and microscopy were used to assess the effect of retinol against asexual stages of the parasite life-cycle. Losses of retinol and retinol-associated hemolysis were also quantified in the in vitro culture system. There were retinol losses of >50% but no hemolysis was observed with added retinol concentrations up to 100 μM. All stages of parasite development showed comparable sensitivity to retinol including merozoite invasion (range of mean IC 50 values 10.1–21.4 μM after adjustment for losses). Retinol pre-treatment of uninfected RBC did not inhibit merozoite invasion. Retinol treatment was associated with increased vacuolization within the parasite food vacuole and evidence of parasite membrane rupture. These appearances were similar to those seen with quinoline and artemisinin compounds. Although these data do not support a role for acute retinol supplementation in the treatment of falciparum malaria, they add to knowledge regarding potential antimalarial therapies and justify assessment of more potent synthetic retinoids and their metabolites.

Treatment of the rat hepatic stellate cell line, PAV-1, by retinol and palmitic acid leads to a convenient model to study retinoids metabolism

The main site of vitamin A storage in the liver is the hepatic stellate cells (HSC). Involvement of HSC in vitamin A metabolism has mainly been studied using primary culture, which represents the most physiological model but technically suffers several drawbacks (yield, low reproducibility, etc.). To circumvent these problems, we have previously established and characterised an immortalised rat HSC line named PAV-1. This study aimed to investigate in PAV-1 and in primary HSC (i) the incorporation of retinol and its esterification, (ii) the cellular retinol-binding protein (CRBP) content, (iii) the acid retinyl ester hydrolase activity (aREH), (iv) the thermal susceptibility and (v) the lipid composition of the membranes, which may play a crucial role in retinol transport across cellular membrane. In routine conditions of culture, the rate of retinol esterification in PAV-1 was low (5.2%) compared to that obtained with primary HSC (69.9%). Retinol pre-treatment doubled this esterification rate (10.7%) and the CRBP content in PAV-1. The co-incubation with retinol and palmitic acid enabled PAV-1 to esterify retinol with a rate close to that of primary HSC (66.2% vs. 69.9%) and with similar retinyl ester profiles. aREH activity was higher in primary HSC than in PAV-1. Thermal susceptibility and phospholipid composition of membranes in PAV-1 treated cells were similar to those of primary HSC. In conclusion, our study shows that PAV-1 cells treated with retinol and palmitic acid is a sound and convenient model for studying vitamin A mobilisation, a fundamental physiological event occurring in HSC.

The effect of retinol on hepatic and renal drug-metabolising enzymes

Retinol pretreatment (75 mg/kg/day, 4 days) potentiated paracetamol-induced hepatotoxicity in BALB/c mice (alanine aminotransferase (ALT) activity; 2510 ± 602 vs 1155 ± 282 IU/l; retinol+paracetamol vs corn oil+paracetamol, respectively, P<0.05); however, this potentiation did not occur in the kidney, indicating an organ-specific response. Retinol treatment alone was not toxic in either organ, as indicated by ALT activity, blood urea nitrogen and creatinine. The potentiation effect could be mediated by retinol's induction of CYP450 isoforms relevant to paracetamol metabolism or through depletion of glutathione. Therefore, these parameters were investigated in both organs. Following retinol treatment, renal CYP2E1 and hepatic CYP1A2 and CYP2E1 catalytic activities and polypeptide levels were unchanged. However, retinol significantly decreased both the catalytic activity (0.23 ± 0.03 vs 0.53 ± 0.06 nmol/mg/min; retinol vs untreated, respectively, P<0.05) and polypeptide levels (58 ± 0.6% of control) of hepatic CYP3A. Inhibition of renal CYP3A did not occur as catalytic activity and polypeptide levels were unchanged from control. Following retinol treatment, total reduced glutathione levels, in both organs, were not significantly different from control. Therefore, the potentiation of paracetamol-induced hepatotoxicity is independent of CYP450 and glutathione.

Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse.

In the mouse, retinol administration attenuates carbon tetrachloride (CCl4)-induced hepatic injury. We have investigated the role of cytochrome P4502E1 (CYP2E1) in this interaction. Male Swiss Webster mice were administered retinol (75 mg/kg/d) or vehicle for 3 days prior to CCl4 (30 microl/kg, ip). Hepatotoxicity produced by CCl4 was assessed by plasma alanine aminotransferase (ALT) activity and light microscopy (ALT activity of 1391+/-430 vs. 274+/-92 IU/L for vehicle + CCl4 and retinol + CCl4 treatments respectively, p < 0.05). Retinol's attenuation of liver injury was maintained when CCl4 was administered 48 h after the conclusion of the retinol pretreatment. Aniline hydroxylation activity, an indicator of CYP2E1 catalytic activity, determined on day 4 was 33.8% of untreated control in vehicle + CCl4 treatments while the retinol + CCl4 treatment group was 94.2% of untreated control. Additionally, CYP2E1 immunoreactive protein was 78% lower in vehicle + CCl4 vs. retinol + CCl4 treatment groups. Attenuation of potentiated hepatotoxicity was also observed when CYP2E1 was induced by acetone (ALT activity of 3119+/-1066 vs. 247+/-77 IU/L for vehicle and retinol treatments respectively, p < 0.05). In the mouse, retinol itself does not alter constitutive or inducible CYP2E1 expression. However, in combination with CCl4 retinol does reduce the amount of CCl4 bioactivated to its toxic metabolite. We conclude that retinol attenuates CCl4-induced hepatotoxicity by causing a decrease in CCl4 bioactivation but does not cause a decrease in CYP2E1 expression.

Tolerance Induced by All-trans-Retinol to the Hepatotoxic Effects of Cadmium in Rats: Role of Metallothionein Expression

Recently, it has been shown that large doses of all-trans-retinol (vitamin A) can potentiate the hepatotoxicity of several organic chemicals in the rat. Whether retinol pretreatment can alter the acute hepatotoxicity of an inorganic chemical, such as cadmium, is unknown. Therefore, the objective of this study was to determine how retinol might affect the acute toxicity of cadmium chloride (CdCl2) and to elucidate possible mechanisms. Cadmium exposure can induce acute, lethal hepatocellular necrosis in rodents, as well as lesions in the lung, kidney, testis, and gastrointestinal tract. In the present studies, male Sprague–Dawley rats were pretreated with retinol (75 mg/kg/day, po) for 7 consecutive days. One day after the last dose of retinol, animals were given a single injection of CdCl2(2.5 to 4.0 mg/kg, iv). Cadmium chloride administration to unpretreated control rats caused extensive hepatic, renal, pulmonary, and testicular toxicity at 6, 24, and 48 hr postdosing as evaluated by plasma enzymes and/or histopathology. In retinol-pretreated rats, a significant attenuation of CdCl2-induced tissue injury was observed. Since the inducible cadmium-binding protein metallothionein (MT) is often an essential aspect of cadmium tolerance, its content in tissue was assessed using the cadmium–hemoglobin assay. Interestingly, retinol pretreatment significantly increased MT in the liver by sevenfold, but had no effect on lung, kidney, testicular, or pancreatic MT content. Although this increase in hepatic MT was much less than that induced by CdCl2, it was additive to the induction of CdCl2. Furthermore, the tissue distribution of cadmium was significantly altered by retinol pretreatment. The liver accumulated more cadmium, while less cadmium was found in the lung, kidney, and testis in retinol-pretreated rats than in controls. In monolayers of primary isolated hepatocytes, CdCl2-induced toxicity was significantly reduced in cells isolated from retinol-pretreated rats compared to those isolated from control rats. The dose response was shifted to the right and thein vitrocadmium LC50 was increased byin vivoretinol exposure from 1.1 ± 0.1 to 2.4 ± 0.04 μm. From these data it is concluded that the induction of hepatic MT is an essential aspect of retinol-induced tolerance to CdCl2hepatotoxicity, as well as toxicity in other tissues.

The Role of Inflammatory Cells and Cytochrome P450 in the Potentiation of CCl4-Induced Liver Injury by a Single Dose of Retinol

Evidence suggests that 7 days of retinol pretreatment potentiates chemical-induced liver injury by a mechanism that involves activation of Kupffer cells (KC). These studies were designed to determine if shorter dosing regimens of retinol potentiate carbon tetrachloride (CCl4). Initially, a single dose of retinol was shown to potentiate the hepatotoxicity of CCl4. Male Sprague–Dawley rats were pretreated with all-trans-retinol (75 mg/kg p.o.) 24 hr prior to KC isolation or administration of CCl4(0.2 ml/kg i.p.). KC isolated at 24 hr after retinol released increased amounts of superoxide anion when stimulated with zymosan or phorbol myristate acetate. At 24 hr after CCl4, plasma ALT activities and histological sections of liver were examined. Retinol-pretreated rats showed a significant elevation in both enzyme leakage and centrilobular to midzonal necrosis compared to retinol vehicle controls following CCl4. Although complete protection was not seen, depletion of KC or neutrophils (PMNs) (by gadolinium chloride (GdCl3) or a PMN-depleting antibody, respectively) significantly reduced the hepatotoxicity of 1 day retinol/CCl4liver injury. Immunohistochemical analysis of livers showed significant elevations in positive staining for ED2, ED1, and HIS48 in retinol-pretreated rats given CCl4. GdCl3effectively reduced ED2 staining but did not greatly affect HIS48 staining. Additional studies were performed to estimate the effect of retinol on noninflammatory processes. While total cytochrome P450 was not increased, the activity and concentration of CYP2E1 were both significantly elevated after a single dose of retinol. Hepatocytes isolated from 1-day retinol-treated rats were also more susceptible to CCl4injury, a consequence that is most likely related to elevated CYP2E1 activity. These findings suggest that a single pretreatment with retinol may potentiate CCl4hepatotoxicity by multiple mechanisms which involve increased biotransformation and inflammatory cell activities.

Modulation of chemical-induced lung and liver toxicity by all- trans-retinol in the male Sprague-Dawley rat

We have previously shown that retinol pretreatment limits the amount of pulmonary injury caused by 1-nitronaphthalene in male Sprague-Dawley rats. The main objective of this study was to determine if retinol pretreatment can protect the lung from the toxicity of other systemic pneumotoxicants. Furthermore because retinol has been shown to alter the hepatotoxicity of several chemicals, a secondary objective was to evaluate its effects on the liver injury caused by these toxicants. Rats were pretreated with all- trans-retinol (75 mg/kg/day p.o.) for 1 week, and given 2-nitronaphthalene (200 mg/kg i.p.) or paraquat (25 mg/kg i.p.). At 24 h after 2-nitronaphthalene treatment, pulmonary morphological changes associated with the bronchiolar epithelium, as well as a moderate pneumonitis were observed. Pretreatment of rats with retinol inhibited the majority of 2-nitronaphthalene-induced pulmonary damage including the infiltration of inflammatory cells and associated edema. However, these animals possessed limited lesions associated with their non-ciliated bronchiolar epithelial (Clara) cells. Interestingly, pretreatment with retinol also caused a significant potentiation of 2-nitronaphthalene-induced liver damage. The potentiated hepatotoxicity consisted of centrilobular hepatocyte necrosis with infiltration of inflammatory cells. Gadolinium chloride (GdCl 3), an inhibitor of Kupffer cell function, significantly decreased the potentiated hepatocellular injury. In paraquat-treated rats focal areas of damage to the alveolar parenchyma, consisting of inflammatory cell infiltration and alveolar sac remodeling, were observed at 48 h. Pretreatment with retinol caused significant protection from the pulmonary damaged caused by paraquat. Specifically, there was a lack of alveolar parenchymal cell damage and inflammatory cell infiltration in these animals. From these experiments, we conclude that retinol pretreatment decreases the severity of 2-nitronaphthalene and paraquat-induced pulmonary toxicity, apparently by inhibiting the inflammatory responses associated with the progression of toxic injury. In the liver, retinol potentiated 2-nitronaphthalene-induced hepatotoxicity by a mechanism which directly involves Kupffer cells.

All-trans-Retinol Alteration of 1-Nitronaphthalene-Induced Pulmonary and Hepatic Injury by Modulation of Associated Inflammatory Responses in the Male Sprague-Dawley Rat

Large doses of retinol (vitamin A) have been shown to potentiate the hepatotoxicity of several chemicals in rats. The objective of this study was to determine how retinol would affect the pulmonary and hepatic toxicity caused by 1-nitronaphthalene (1-NN). All-trans-retinol (75 mg/kg/day, po) was administered for 7 days to male Sprague-Dawley rats. One day after the last dose of retinol, animals were given a single injection of 1-NN (100 mg/kg, ip). At 24 hr, animals receiving retinol vehicle and 1-NN exhibited respiratory distress syndrome and chromodacryorrhea. Pulmonary morphological changes included necrosis and exfoliation of the bronchiolar epithelium, as well as infiltration of inflammatory cells into the interstitial areas around affected bronchioles. The bronchioalveolar lavage fluid from these animals exhibited significant increases in the activities of gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), as well as protein and inflammatory cell content. Following pretreatment with retinol, none of the animals treated with 1-NN exhibited outward signs of toxicity. In addition, the lavage fluid of these rats revealed significant reductions in inflammatory cells, protein, and LDH activity. However, lavage fluid GGT activity was significantly increased. Morphological evaluation of the lungs revealed nonciliated bronchiolar epithelial (Clara) cell damage with no associated inflammation. Retinol pretreatment resulted in potentiated hepatotoxicity as indicated by increases in plasma alanine aminotransferase and GGT activities, as well as plasma total bilirubin. The altered plasma enzyme activities correlated with increased hepatocyte and bile duct epithelial necrosis, as well as an increased infiltration of neutrophils into the areas around bile ducts. Retinol potentiation of 1-NN-induced hepatocyte necrosis was significantly reduced following pretreatment with gadolinium chloride (GdCl3). From these experiments, we conclude that in the lung pretreatment with retinol decreased the severity of 1-NN-induced toxicity apparently by an anti-inflammatory mechanism. In the liver, retinol potentiated 1-NN-induced liver injury apparently through a proinflammatory mechanism by activating Kupffer cells and increasing the infiltration of neutrophils into the periportal regions adjacent to bile ducts.

The Interactions between Retinol and Five Different Hepatotoxicants in the Swiss Webster Mouse

The Interactions between Retinol and Five Different Hepatotoxicants in the Swiss Webster Mouse. Rosengren, R. J., Sauer, J.-M., Hooser, S. B., and Sipes, I. G. (1995). Fundam. Appl. Toxicol. 25, 281-292. The interactive effects between retinol and various hepatotoxicants (allyl alcohol, acetaminophen, carbon tetrachloride, D-galactosamine, and phalloidin) were studied in the male Swiss Webster mouse. The mice were administered retinol at 75 mg/kg/day (or the vehicle of retinol) by oral gavage for 7 days. Hepatoxicity produced by the chemicals was determined by plasma alanine aminotransferase (ALT) activity and histopathology. After 7 days of retinol pretreatment, the hepatotoxicities of allyl alcohol, acetaminophen, and galactosamine were potentiated. Interestingly, the hepatotoxicity of carbon tetrachloride and phalloidin was protected by identical retinol pretreatment. Microscopic examination of histologic liver sections demonstrated the specific hepatic necrosis associated with each individual chemical and confirmed the ALT values obtained. Once an interaction between retinol and the five hepatotoxicants was established, the duration of retinol pretreatment necessary to elicit an interaction was determined for each hepatotoxicant. Results demonstrated that the duration of retinol pretreatment was specific for each hepatotoxicant. The accumulation of retinoids in the liver during retinol pretreatment was determined using high-performance liquid chromatography analysis. Significant increases in the basal liver levels of retinol and retinyl palmitate were seen within 1 to 3 days of retinol treatment compared to control. Retinol pretreatment resulted in potentiation or protection of specific hepatotoxicant-induced liver damage. Currently, studies are being conducted which probe into the mechanisms of these interactions.

Alterations in Chemically Induced Tissue Injury Related to All-trans-Retinol Pretreatment In Rodents

Retinol (vitamin A) is an essential nutrient which has many physiological effects throughout the body. Our studies have demonstrated that retinol modulation of immune response, through alteration of macrophage and neutrophil function, can have dramatic effects on the toxicity of some compounds. Based on these studies, our current hypothesis for retinol potentiation of chemical-induced liver injury is that retinol administered to rats prior to the hepatotoxicant (CCl4 and AA in rats; and AA, APAP, and GalN in mice) primes the Kupffer cells to a more active state. This may occur in part as a result of increases in chemical mediators such as TNF from these Kupffer cells. Following hepatocyte damage by a toxicant, Kupffer cells are activated to release reactive oxygen species, immune mediators, and chemotactic factors which all serve to enhance the inflammatory response. This increased inflammatory response then results in increased injury to the already toxicant-damaged hepatocytes. In addition, retinol modulation of toxicant activation and detoxification may also make important contributions to the potentiation of some toxicants such as AA. Retinol protection of CCl4 hepatotoxicity in mice is more difficult to explain at this time but is possibly related to alterations in CCl4 metabolism in this species. Differences in response between pulmonary and liver macrophages (Kupffer cells) may explain the retinol protection from 1-NN pulmonary toxicity. Retinol may decrease the inflammatory response through downregulation of pulmonary macrophage function, thus resulting in decreased pulmonary injury. Finally, since retinol protection of cadmium toxicity in the liver and testis requires 7 days of retinol pretreatment, we suspect that retinol is inducing protective protein(s) in these organs. Aside from its normal biological role in rhe body, clinical medicine has found new uses for retinol in the treatment and prevention of some cancers, and in the treatment of certain dermatologic conditions. Since these patients are frequently administered or exposed to other potentially toxic compounds, it is obviously prudent and necessary to continue research into the effects of retinol on immune modulation and interaction with other compounds. More importantly, these studies demonstrate the modulation of immune function is one mechanism by which one chemical can influence the toxicity of another.

Pretreatment with vitamin A inhibits transforming growth factor alpha stimulation of human mammary carcinoma cells.

Vitamin A or retinol is an important agent in the normal differentiation and growth of cells. Retinol is an effective inhibitor of the growth of many transformed cells in vitro and in vivo but its mechanism of action is unclear. Transforming growth factor alpha (TGF alpha) is a known mitogen. We examined the effect of retinol treatment on TGF alpha stimulation of two human mammary carcinoma cell lines, one which is growth inhibited by retinol and one which is not. Pretreatment of both cell lines for 48 hours with retinol resulted in inhibition of TGF alpha stimulation of growth. In the T47D cell line the mechanism was not related to an effect on the cellular content of TGF alpha, epidermal growth factor (EGF) receptor protein, EGF receptor mRNA, or on the binding of TGF alpha to the EGF receptor. However, TGF alpha-induced stimulation of the EGF receptor substrate, phospholipase C-gamma 1, was abrogated in the T47D cell line with retinol pretreatment. In the MDA-MB-468 cell line, pretreatment with retinol resulted in a decrease in tyrosine phosphorylation of the EGF receptor. These results suggest that pretreatment with retinol decreases cellular proliferation seen with TGF alpha treatment by altering phospholipase C-gamma 1 response and/or EGF receptor tyrosine kinase activity. Alteration of phospholipase C-gamma 1 activity does not appear to be responsible for the inhibition of cell growth seen in the absence of TGF alpha stimulation.