Evaluation of the Atherogenic Risk of Isotretinoin-induced and Etretinate-induced Alterations of Lipoprotein Cholesterol Metabolism.

Melnik, Bodo C.; Bros, Uwe; Plewig, Gerd

doi:10.1111/1523-1747.ep12468920

Cited by 13 publications

(3 citation statements)

References 30 publications

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“…Only kinetic studies o f VLDL turnover will provide lacking information. Because of the increase of total serum apo B, LDL cholesterol, and decreased HDL cholesterol, especially HDL; choles terol, a long-term use of isotretinoin may result in an increased risk of cardiovascular disease [54]. The quotient of total cholester ol and HDL cholesterol, a well accepted epidemiological risk factor of cardiovas cular disease, increased in our study from 3.73 ±1.16 to 4.33 ±0.94 (p < 0.025).…”

Section: Discussionmentioning

confidence: 43%

Characterization of Apoprotein Metabolism and Atherogenic Lipoproteins during Oral Isotretinoin Treatment

Melnik¹,

Bros²,

Plewig³

1987

Dermatology

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Apoprotein, lipoprotein and lipid parameters of 36 normolipidemic subjects (23 males, mean age 22.7 ± 7.6 years; 13 females, mean age 26.2 ± 9.8 years) receiving oral isotretinoin (mean daily dose 0.73 ± 0.26 mg/kg body weight) for nodulocystic acne (n = 18), severe acne papulopustulosa (n = 15), gram-negative folliculitis (n = 2) and papulopustular rosacea (n = l) were monitored before and during isotretinoin therapy at biweekly intervals over a period of 14.6 ± 5.6 weeks. Pretreatment values of mean plasma triglycerides increased significantly (p < 0.001) from 81.8 ± 31.9 mg/dl to 112.4 ± 38.7 mg/dl (47.4%) during isotretinoin treatment. With respect to the mean percent increase of plasma triglycerides from pretreatment levels, patients were classified as nonresponders ( < 10% triglyceride increase), responders ( > 10% < 50% triglyceride increase) and hyperresponders ( > 50% triglyceride increase), revealing a distribution of 25.0, 36.1 and 38.9%, respectively. Isotretinoin treatment had no influence on the isoelectric focusing pattern of apoprotein E isoforms and C apoproteins. In particular, apoprotein C-II, the cofactor of lipoprotein lipase, was not affected. No correlation between apoprotein E phenotypes (2/3, 3/3, 3/4) and the mean plasma triglyceride increase could be demonstrated. Apoprotein B-48, a marker of chylomicrons and atherogenic chylomicron remnants, could not be detected by SDS-PAGE. On the other hand in 21.0% of patients with preexisting mean lipoprotein Lp(a) levels of 18.1 ± 12.9 mg/dl a moderate increase of atherogenic Lp(a) to mean levels of 37.0 ± 22.0 mg/dl was observed. Pretreatment values of very-low-density lipoprotein (VLDL) apoprotein (apo) B (7.5 ± 2.0 mg/dl), low-density lipoprotein apo B (67.3 ± 17.5 mg/dl) and total plasma apo B (76.6 ± 19.0 mg/dl) increased significantly to levels of 10.3 ± 2.4 mg/dl (p < 0.001), 75.7 ± 15.8 mg/dl (p < 0.10) and 85.9 ± 17.7 mg/dl (p < 0.05), respectively. As lipoprotein lipase and hepatic lipase activities have been shown to be unaffected by isotretinoin treatment, our data support the hypothesis that isotretinoin induces hepatic oversecretion of VLDL, a condition resembling type IV hyperlipidemia in diabetics, familial hypertriglyceridemia or familial combined hyperlipidemia.

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Section: Discussionmentioning

confidence: 43%

Characterization of Apoprotein Metabolism and Atherogenic Lipoproteins during Oral Isotretinoin Treatment

Melnik¹,

Bros²,

Plewig³

1987

Dermatology

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“…In humans, the synthetic retinoids, isotretinoin (13-cis retinoic acid) and etretinate (aromatic retinoid) induce significant increases in triglycerides, total and LDL cholesterol, but they have an opposite effect on HDL, leading to concentrations decreased by 10-24% (Zech et al 1983, Melnik et al 1987. These retinoid-induced alterations are felt to be detrimental because of a more atherogenic lipid profile that thus exposes the patients to the risk for developing premature cardiovascular disease.…”

Section: Retinoic Acidsmentioning

confidence: 99%

Hormonal regulation of apolipoprotein AI

Hargrove¹,

Junco²,

Wong³

1999

Journal of Molecular Endocrinology

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Apolipoprotein AI (apo AI) is the major protein component of the serum high-density lipoprotein (HDL) particles. The antiatherogenic properties of apo AI alone or as part of HDL and their inverse correlation with the incidence of coronary heart disease underlie the clinical importance of the protein. A detailed understanding of the mechanisms by which apo AI is regulated will help us develop new and better ways to manipulate expression of the protein. Although there are many factors that influence apo AI expression, endogenous hormones are attractive because simple changes in abundance of these compounds will alter gene activity. Hormones belonging to the thyroid/steroid family that influence activity of the gene include thyroid hormone, glucocorticoids, gender-specific steroids and retinoic acid. Whereas thyroid, glucocorticoid and estradiol enhance activity of the gene, retinoic acid and androgens decrease it. The mechanisms that mediate the effects of the hormones include direct effects of the ligand and nuclear receptor complex on gene activity. However, indirect means involving the participation of transcription factors other than the hormone receptors are also possible. In summary, members of the same hormone family may have different mechanisms that mediate their activities on apo AI gene activity.

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“…In fact, TRAIL has been demonstrated to play a critical role in hepatic cell death and hepatic inflammation (97). Isotretinoin-mediated FoxO1 signalling may also explain isotretinoin-induced hypertriglyceridaemia (30,98,99). FoxO1 upregulates microsomal triglyceride transfer protein, which increases hepatic synthesis of triglyceride-rich VLDL (100,101).…”

Section: Hepatocyte Apoptosismentioning

confidence: 99%

Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity

Melnik

2017

Acta Derm Venerol

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Isotretinoin (13-cis retinoic acid) is the most effective sebum-suppressive drug for the treatment of severe acne. Its effect depends on sebocyte apoptosis, which results from isotretinoin-induced expression of the apoptotic protein tumour necrosis factor-related apoptosis-inducing ligand, insulin-like growth factor-binding protein-3 and neutrophil gelatinase-associated lipocalin. This review proposes that the pharmacological mode of action of isotretinoin in the treatment of severe acne, acute promyelocytic leukaemia, and neuroblastoma results from apoptosis. Furthermore, apoptosis may be the underlying and unifying mechanism of the adverse effects of isotretinoin on neural crest cells (teratogenicity), hippocampal neurones (depression), epidermal keratinocytes and mucosa cells (mucocutaneous side-effects), hair follicle cells (telogen effluvium), intestinal epithelial cells (inflammatory bowel disease), skeletal muscle cells (myalgia and release of creatine kinase), and hepatocytes (release of transaminases and very low-density lipoproteins). Genetic variants of components of the apoptotic signalling cascade, such as RARA polymorphisms, might explain variations in the magnitude of isotretinoin-induced apoptotic signalling and apparently identify subgroups of patients who experience either stronger adverse effects with isotretinoin therapy or resistance to treatment.

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Evaluation of the Atherogenic Risk of Isotretinoin-induced and Etretinate-induced Alterations of Lipoprotein Cholesterol Metabolism.

Cited by 13 publications

References 30 publications

Characterization of Apoprotein Metabolism and Atherogenic Lipoproteins during Oral Isotretinoin Treatment

Characterization of Apoprotein Metabolism and Atherogenic Lipoproteins during Oral Isotretinoin Treatment

Hormonal regulation of apolipoprotein AI

Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity

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