Mechanism of Action of Tretinoin Cream
Tretinoin cream works by decreasing the cohesiveness of follicular epithelial cells, which prevents microcomedone formation, while simultaneously stimulating mitotic activity and increased turnover of follicular epithelial cells to extrude existing comedones. 1
Primary Cellular Mechanisms
Tretinoin exerts its effects through binding to nuclear retinoic acid receptors (RARα, RARβ, and RARγ), which act as transcriptional factors for specific DNA sequences. 2 These receptors are part of the steroid-thyroid hormone superfamily and mediate the drug's diverse effects on skin cells. 3
The key cellular actions include:
- Normalization of follicular epithelial cell differentiation by reducing abnormal cohesiveness between cells, which is the fundamental defect in acne and other keratinization disorders 1
- Acceleration of epidermal cell turnover through stimulation of mitotic activity, causing the physical extrusion of comedones from follicles 1
- Anti-inflammatory effects through inhibition of inflammation mediators, though this is secondary to the primary keratolytic action 3
Effects on Skin Structure
Beyond the follicular effects, tretinoin produces broader changes in skin architecture:
- Epidermal remodeling including thickening of the epidermis, increased granular layer thickness, and stratum corneum compaction 4
- Dermal collagen synthesis with increased production of types I and III procollagen, which remedies collagen deficiency in photodamaged skin 3
- Dermal matrix reconstruction with improvement in the dermoepidermal junction and correction of keratinocyte degeneration, changes that become evident after 12 months of continuous use 4
- Reduction in melanin content contributing to improvement in dyspigmentation 4
Clinical Translation of Mechanism
The comedolytic and microcomedone-preventing actions make tretinoin the cornerstone of acne therapy, as it addresses the precursor lesion to all acne types. 5 This explains why tretinoin is effective for both comedonal and inflammatory acne variants. 6
For photodamaged skin, the collagen synthesis and dermal reconstruction mechanisms account for the moderate improvements in fine wrinkles, roughness, and pigmentation observed in clinical trials. 4, 7
Important Mechanistic Caveats
Tretinoin is photolabile and undergoes oxidation when exposed to light or combined with benzoyl peroxide, which inactivates the medication. 5 This chemical instability necessitates evening application and separation from oxidizing agents.
The mechanism of accelerated cellular turnover predictably causes local irritation (erythema, dryness, peeling, scaling, burning) during the first 2-4 weeks of treatment. 8, 9 This is not an allergic reaction but rather the expected pharmacologic effect of increased epidermal turnover. The irritation typically subsides as the skin adapts to the increased cellular activity.
Initial worsening may occur between 3-9 weeks before clinical improvement is seen, particularly when treating actinic keratoses. 6 This reflects the time required for abnormal cells to be expelled and replaced with normalized epithelium.
The keratolytic mechanism also explains tretinoin's efficacy in disorders of keratinization beyond acne, including keratosis pilaris, ichthyosis, and Darier disease, where it normalizes abnormal follicular keratinization patterns. 9